Imidazolidinones and analogs exhibiting anti-cancer and anti-proliferative activities

ABSTRACT

Described are compounds of Formula I 
     
       
         
         
             
             
         
       
     
     which find utility in the treatment of cancer, autoimmune diseases and metabolic bone disorders through inhibition of c-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also find utility in the treatment of other mammalian diseases mediated by c-FMS, c-KIT, or PDGFR kinases.

PRIORITY Cross-Reference to Related Applications

This application is a divisional application under 35 U.S.C. §120, ofU.S. application Ser. No. 14/214,134, which was filed on Mar. 14, 2014,which in turn claims the benefit of U.S. Provisional Application No.61/788,374, filed Mar. 15, 2013. The entire disclosure of thisapplication is relied on and incorporated into this application byreference.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith areincorporated herein by reference in their entirety: A computer readableformat copy of the Sequence Listing (filename: DECP_(—)053_(—)01US_SeqList_ST25.txt, date recorded: Mar. 12, 2014, file size 18kilobytes).

FIELD OF THE INVENTION

Disclosed are compounds which find utility in the treatment of cancer,autoimmune diseases and metabolic bone disorders through inhibition ofc-FMS (CSF-1R), c-KIT, and/or PDGFR kinases. These compounds also findutility in the treatment of other mammalian diseases mediated by c-FMS,c-KIT, or PDGFR kinases.

BACKGROUND

Autoimmune diseases, including autoimmune arthritis, representsignificant human diseases of high morbidity and prevalence. Rheumatoidarthritis affects ˜0.6% of the world population (Firestein, G. S.,Nature (2003) 423: 356). While the adaptive immune response, involvinggeneration of auto-antibodies which react with tissue antigen, isinvolved in the etiology and initial propagation of these diseases(Edwards, J. C. et al., New England Journal of Medicine (2004) 350:2572; Genovese, M. C. et al., New England Journal of Medicine (2005)353: 1114), the chronic manifestations of tissue and joint damage aremediated in large part by cellular events mediated by the innate immuneresponse (Firestein, G. S., Nature (2003) 423: 356; Paniagua, R. T. etal., Arthritis Research & Therapy (2010) 12: R32). Contributing celltypes from the innate immune response which mediate chronic tissuedamage include fibroblast-like synoviocytes, macrophages, mast cells,and osteoclasts.

Kinases represent a protein family that play critical roles in mammaliancell function, including cell proliferation, survival, motility,response to growth factors, and secretion of cytokines and otherproinflammatory, proangiogenic, and immunomodulatory substances. Thus,elucidation of kinases which mediate these events in fibroblast-likesynoviocytes, macrophages, mast cells, and osteoclasts represents arational approach to new therapies for the treatment of autoimmunediseases.

Imatinib is a marketed kinase inhibitor for the treatment of the cancerchronic myelogenous leukemia (CML, Druker, B. J. et al., New EnglandJournal of Medicine (2001) 344: 1031) and for the treatment ofgastrointestinal stromal tumors (GIST, Demetri, G. D., et al., NewEngland Journal of Medicine (2002) 347: 472). Imatinib has also shownbenefit in cancer patients co-presenting with autoimmune diseases suchas rheumatoid arthritis (Ihara, M. K. et al., Clinical Rheumatology(2003) 22: 362; Eklund, K. K. and Joensuu, H., Ann Medicine (2003) 35:362; Ames, P. R. et al., Journal of Rheumatology (2008) 35: 1682). Thekinases inhibited by imatinib which confer its efficacy in the treatmentof CML and GIST are BCR-ABL kinase and c-KIT kinase, respectively.Beyond these two kinases, other kinases inhibited by imatinib includec-FMS, PDGFR-alpha, and PDGFR-beta (Dewer, A. L. et al., Blood (2005)105: 3127; Fabian, M. A. et al., Nature Biotechnology (2005) 23: 329.

Recent research disclosures have identified c-FMS kinase to beassociated with activation of synovial macrophages, PDGFR kinase to beassociated with activation of fibroblast-like synoviocytes, and c-KITkinase to be associated with activation of mast cells (Paniagua, R. T.,et al Journal of Clinical Investigation (2006) 116: 2633). c-FMS kinasehas also been associated with the proliferation and differentiation ofmonocytes into macrophages and osteoclasts, which are recruited tomediate joint damage in rheumatoid arthritis (Paniagua, R. T. et al.,Arthritis Research & Therapy (2010) 12: R32; Yao, Z. et al., Journal ofBiological Chemistry (2006) 281: 11846; Patel, S. and Player, M. R.Current Topics in Medicinal Chemistry (2009) 9: 599; Pixley, F. J. etal., Trends in Cell Biology (2004) 14: 628).

In recent years, the importance of the tumor microenvironment in cancermotility, invasion, and metastasis has become more clearly defined.Specifically, the role of tumor-associated macrophages (TAMs) in tumorprogression has been studied. These host (stromal) macrophages arerecruited to tumor sites or to pre-metastatic niches to modify the tumorenvironment and render that environment more conducive to tumormotility, invasion and metastasis. These TAMs are known to express c-FMSreceptor tyrosine kinase (also known as CSF-1R) on their surfaces and torely on signaling through this kinase by binding to the activatingligands CSF-1 (also known as macrophage colony stimulating factor, orMCSF) and interleukin-34 (IL-34). Activation of this c-FMS/MCSF(CSF1-R/CSF-1) signaling axis stimulates monocyte proliferation,differentiation into tumor associated macrophages, and promotion ofmacrophage cell survival. By stimulating the TAM component of the tumormicroenvironment, c-FMS kinase activation is associated with tumor cellmigration, invasion, and metastasis (J. Condeelis and J. W. Pollard,Cell (2006) 124: 263; S. Patel and M. R. Player, Current Topics inMedicinal Chemistry (2009) 9: 599). Ablation of CSF-1, the ligand forc-FMS kinase, in mice reduced tumor progression and significantlyreduced metastasis in a murine model of breast cancer; whereasoverexpression of CSF-1 accelerated metastasis in this model (E. Y. Linet al., Journal of Experimental Medicine (2001) 193: 727). Furthermore,an interaction between tumor cells and macrophages has been described,wherein macrophage secretion of the tumor growth factor EGF and tumorcell secretion of CSF-1 establish a paracrine loop that promotes tumormigration and invasiveness. This paracrine loop was blocked byadministration of an antibody to the c-FMS kinase (J. Wyckoff et al.,Cancer Research (2004) 64: 7022). Correlative clinical data have alsoshown that overexpression of CSF-1 in tumors is a predictor of poorprognosis (R. D. Leek and A. L. Harris, Journal of Mammary Gland BiologyNeoplasia (2002) 7: 177; E. Y. Lin et al., Journal of Mammary GlandBiology Neoplasia (2002) 7: 147). c-FMS kinase activation is alsorequired for osteoclast differentiation and activation. Its involvementin mediating bone metastases of various cancers, including breast andprostate cancers, has been reported (S. Patel and M. R. Player, CurrentTopics in Medicinal Chemistry (2009) 9: 599). High plasma concentrationsof CSF-1 have been reported in bone metastatic prostate cancer,implicating activation of osteoclast c-FMS kinase in prostate cancerbone metastases (H. Ide, et al., Human Cell (2008) 21: 1). c-FMSinhibitors have been reported to reduce radiographic bone lesions whenevaluated in models of metastatic bone disease (C. L. Manthey, et al.,Molecular Cancer Therapy (2009) 8: 3151; H. Ohno et al., Mol. CancerTherapy (2006) 5: 2634). MCSF-mediated activation of both LYVE-1+ andLYVE1− macrophages also mediates pathological angiogenesis andlymphangiogenesis in murine models of cancer, and blockade of c-FMSsignaling resulted in suppression of tumorangiogenesis/lymphangiogenesis (Y. Kubota et al., Journal ofExperimental Medicine (2009) 206: 1089). Administration of a CSF-1Rinhibitor blocked the recruitment of bone marrow derived TAMs and alsobone marrow derived monocytic myeloid-derived suppressor cells (MDSCs)to tumor sites; this blockade led to a significant decrease in tumorangiogenesis and when combined with anti-VEGFR-2 therapy synergisticallysuppressed tumor growth (S. J. Priceman, et al., Blood (2010) 115:1461). Irradiation of glioblastoma tumors in mice was shown to cause atemporary decrease in tumor size only to be followed by a rebound tumorvasculogenesis mediated by the recruitment of bone marrow derivedmonocytes expressing CD11b and F4/80 surface antigens (M. Kioi et al.,Journal of Clinical Investigation (2010) 120: 694). CD11b+ and F4/80+monocytes are also known to express functional c-FMS receptors. Hence,blockade of tumor infiltrating c-FMS+ bone marrow derived monocytes bythe use of c-FMS kinase inhibitors offers the potential to prevent tumorrebound vasculogenesis and glioblastoma tumor progression. CSF-1Rblockade has also been shown to reverse immunotolerance mechanisms in animmunocompetent murine breast cancer model and promote the appearance ofanti-tumor immune programs by upregulating CD8+ T-cell-mediated tumorsuppression. Restoration of an anti-tumor immune program wasmechanistically linked to c-FMS inhibitor blockade of TAM-mediatedProgrammed Death Ligand-1 (PDL-1) immunotolerance (D. G. DeNardo, etal., Cancer Discovery (2011) 1: OF52).

Hence, small molecule inhibitors of c-FMS kinase, c-KIT kinase, or PDGFRkinases provide a rational approach to new therapies for the treatmentof autoimmune diseases, and to particularly block the chronic tissuedestruction mediated by the innate immune system. Inhibition of c-FMSkinase also provides a rational approach to new therapies for thetreatment of cancers, especially for the treatment of cancerinvasiveness, cancer angiogenesis or vasculogenesis, cancer metastasis,cancer immunotolerance, and for the treatment of cancers prone to bonemetastases.

There is a need to provide kinase inhibitors which selectively inhibitkinases causative of the chronic tissue destruction in autoimmunedisease (c-FMS, c-KIT, PDGFR), without inhibiting other kinases targetedby marketed cancer therapeutics (ABL, BCR-ABL, KDR, SRC, LCK, LYN, FGFRand other kinases). The present invention discloses novel inhibitorsthat inhibit c-FMS, c-KIT, and/or PDGFR kinases for the treatment ofautoimmune diseases which also exhibit selectivity by not potentlyinhibiting other kinases including ABL, BCR-ABL, KDR, SRC, LCK, LYN,FGFR, MET and other kinases. The inhibitors of the present inventionalso find utility in the treatment of other mammalian diseases,including human diseases, mediated by c-FMS, c-KIT, or PDGFR kinases.

Such diseases include, without limitation, cancers, autoimmune diseases,and bone resorptive diseases.

SUMMARY OF THE INVENTION

In one aspect, compounds of the Formula I are described:

and pharmaceutically acceptable salts, enantiomers, stereoisomers, ortautomers thereof,

wherein

A is selected from the group consisting of C1-C6 alkyl, deutero-C1-C6alkyl wherein the alkyl chain is partially or completely deuterated,branched C3-C8alkyl, fluoroC1-C6alkyl wherein the alkyl is fully orpartially fluorinated, C3-C8carbocyclyl, and a 4-8 membered heterocyclicring, and wherein the A moiety may be further substituted with one, two,or three R3 moieties;

W is C5-C6heteroaryl, —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9, —C(O)R11 orphenyl, wherein the C5-C6heteroaryl and phenyl moieties are optionallysubstituted by one, two, or three R5;

each X1, X2, X3 and X4 are individually and independently hydrogen,C1-C6 alkyl, halogen or fluoro-C1-C6 alkyl wherein the alkyl chain ispartially or completely fluorinated;

Z1 is N or CX3;

Z2 is CX4 or N;

Z3 is CH or N;

each R1 and R2 is individually and independently H, C1-C6 alkyl,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,hydroxyl, C1-C6 alkoxy, fluoroC1-C6alkoxy wherein the alkyl group isfully or partially fluorinated, or cyano;

each R3 is individually and independently H, halogen, C1-C6 alkyl,fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy,fluoro-C1-C6 alkoxy wherein the alkyl chain is partially or completelyfluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano;

each R4 is individually and independently hydrogen, C1-C6 alkyl, orbranched C3-C8 alkyl;

each R5 is individually and independently hydrogen, C1-C6 alkyl,deutero-C1-C6 alkyl wherein the alkyl chain is partially or completelydeuterated, branched C3-C8 alkyl, halogen, cyano, fluoro-C1-C6 alkylwherein the alkyl chain is partially or completely fluorinated,—(CH₂)_(m)—C(O)NR8(R9), —(CH₂)_(m)—C(O)R7, —(CH₂)_(m)—C(O)R6,—(CH₂)_(m)—CN, —(CH₂)_(m)—OR8, —(CH₂)_(m)—NR8(R9), or —(CH₂)_(m)—R7,wherein each alkylene may be further substituted with one or moreC1-C6alkyl;

each R6 is individually and independently hydrogen, C1-C6 alkyl,branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH₂)_(m)—OR8,—(CH₂)_(m)—NR8(R9), or —(CH₂)_(m)—R7, wherein each alkylene may befurther substituted with one or more C1-C6alkyl;

each R7 is independently and individually selected from the groupconsisting of

and wherein the symbol (##) is the point of attachment to respective R5or R6 moieties containing a R7 moiety;

each R7 is optionally substituted with —(R10)_(p);

each R8 and R9 is individually and independently H, C1-C6 alkyl,fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated, or branched C3-C8 alkyl;

each R10 is individually and independently C1-C6 alkyl, —(CH₂)_(m)—CN,—(CH₂)_(m)—OR3, —(CH₂)_(m)—NR8(R9), or —(CH₂)_(m)—C(O)—R6, wherein eachalkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;

R11 is —N(R8)R9 or R7;

each m is individually and independently 0, 1, 2, or 3;

each n is individually and independently 0, 1, 2, or 3;

each p is individually and independently 0, 1, 2, or 3; and

each q is individually and independently 0, 1, 2, or 3;

In one embodiment of Formula I, A is C1-C6alkyl.

In one embodiment of Formula I, A is branched C3-C8alkyl.

In one embodiment of Formula I, A is fluoroC1-C6alkyl wherein the alkylis fully or partially fluorinated.

In one embodiment of Formula I, A is C3-C8carbocyclyl.

In one embodiment of Formula I, A is a 4-8 membered heterocyclic ring.

In one embodiment of Formula I, W is C5-C6heteroaryl optionallysubstituted by one, two, or three R5.

In one embodiment of Formula I, W is —NHC(O)R6, —NHC(O)R7, or—NHC(O)N(R8)R9.

In one embodiment of Formula I, W is —NHC(O)R6.

In one embodiment of Formula I, W is —NHC(O)R7.

In one embodiment of Formula I, W is —NHC(O)N(R8)R9.

In one embodiment of Formula I, W is —C(O)R11.

In one embodiment of Formula I, W is phenyl optionally substituted byone, two, or three R5.

In one embodiment of Formula I, Z1 is N, Z2 is CX4, and X1, X2 and X4are individually and independently hydrogen, C1-C6 alkyl, halogen orfluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated.

In one embodiment of Formula I, Z1 is N, Z2 is CX4, and X1, X2 and X4are individually and independently hydrogen or C1-C6 alkyl.

In one embodiment of Formula I, Z1 is N, Z2 is CX4, and X1, X2 and X4are hydrogen.

In one embodiment of Formula I, Z1 is N, Z2 is CX4, X4 is hydrogen, andone of X1 and X2 is hydrogen and the other is C1-C6alkyl.

In one embodiment of Formula I, Z1 is CX3, Z2 is CX4, and X1, X2, X3 andX4 are individually and independently hydrogen, C1-C6 alkyl, halogen orfluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated.

In one embodiment of Formula I, Z1 is CX3, Z2 is CX4, and X1, X2, X3 andX4 are individually and independently hydrogen or halogen.

In one embodiment of Formula I, Z1 is CX3, Z2 is CX4, X1 and X3 arehalogen, and X2 and X4 are hydrogen.

In one embodiment of Formula I, Z1 and Z2 are N, and X1 and X2 areindividually and independently hydrogen or C1-C6 alkyl.

In one embodiment of Formula I, Z1 and Z2 are N, and X1 and X2 arehydrogen.

In one embodiment of Formula I, Z3 is CH.

In one embodiment of Formula I, Z3 is N.

In one embodiment, the compound of Formula I is a compound of Formula Ia

wherein A, X1, X2, W, Z1, R3, R4, n, and p are described above.

In one embodiment of Formula Ia, A is methyl and R3 is H.

In one embodiment of Formula Ia, A is ethyl and R3 is H.

In one embodiment of Formula Ia, A is branched C3-C8alkyl.

In one embodiment of Formula Ia, A is isopropyl and R3 is H.

In one embodiment of Formula Ia, A is tert-butyl and R3 is H.

In one embodiment of Formula Ia, A is fluoroC1-C6alkyl wherein the alkylis fully or partially fluorinated and R3 is H.

In one embodiment of Formula Ia, A is 2,2,2-trifluoroethyl and R3 is H.

In one embodiment of Formula Ia, A is C3-C8carbocyclyl.

In one embodiment of Formula Ia, A is cyclopropyl.

In one embodiment of Formula Ia, A is cyclobutyl.

In one embodiment of Formula Ia, A is cyclopentyl.

In one embodiment of Formula Ia, A is cyclohexyl.

In one embodiment of Formula Ia, A is a 4-8 membered heterocyclic ring.

In one embodiment of Formula Ia, A is a oxetanyl.

In one embodiment of Formula Ia, A is a tetrahydrofuranyl.

In one embodiment of Formula Ia, A is a tetrahydropyranyl.

In one embodiment of Formula Ia, W is C5-C6heteroaryl optionallysubstituted by one, two, or three R5.

In one embodiment of Formula Ia, W is pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W isoptionally substituted by one, two, or three R5.

In one embodiment of Formula Ia, W is pyrazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ia, W is imidazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ia, W is isoxazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ia, W is oxazolyl optionally substituted byone or two R5.

In one embodiment of Formula Ia, W is thiazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ia, W is triazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ia, W is pyridinyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ia, W is —NHC(O)R6, —NHC(O)R7, or—NHC(O)N(R8)R9.

In one embodiment of Formula Ia, W is —NHC(O)R6.

In one embodiment of Formula Ia, W is —NHC(O)R7.

In one embodiment of Formula Ia, W is —NHC(O)N(R8)R9.

In one embodiment of Formula Ia, W is —C(O)R11.

In one embodiment of Formula Ia, W is phenyl optionally substituted byone, two, or three R5.

In one embodiment of Formula Ia, Z1 is N, and X1 and X2 are individuallyand independently hydrogen, C1-C6 alkyl, halogen or fluoro-C1-C6 alkylwherein the alkyl chain is partially or completely fluorinated.

In one embodiment of Formula Ia, Z1 is N, and X1 and X2 are individuallyand independently hydrogen or C1-C6 alkyl.

In one embodiment of Formula Ia is, Z1 is N, and X1 and X2 are hydrogen.

In one embodiment of Formula Ia, Z1 is N, and one of X1 and X2 ishydrogen and the other is C1-C6alkyl.

In one embodiment of Formula Ia, Z1 is CX3, and X1 and X2 and X3 areindividually and independently hydrogen, C1-C6 alkyl, halogen orfluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated.

In one embodiment of Formula Ia, Z1 is CX3, and X1 and X2 and X3 areindividually and independently hydrogen or halogen.

In one embodiment of Formula Ia, Z1 is CX3, and X1 and X3 are halogen,and X2 is hydrogen.

In one embodiment of Formula Ia, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and W is pyrazolyl, imidazolyl, or pyridinyl, andZ1 is N, and X1 is H, and X2 is C1-C6alkyl, and each R3 is independentlyH, C1-C6alkyl or C1-C6alkoxy.

In one embodiment of Formula Ia, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and W is pyrazolyl, imidazolyl, or pyridinyl, andZ1 is N, and X2 is H, and X1 is C1-C6alkyl, and each R3 is independentlyH, C1-C6alkyl or C1-C6alkoxy.

In one embodiment of Formula Ia, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and W is pyrazolyl, imidazolyl, or pyridinyl, andZ1 is N, and X1 and X2 are H, and each R3 is independently H, C1-C6alkylor C1-C6alkoxy.

In one embodiment of Formula Ia, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and W is pyrazolyl, imidazolyl, or pyridinyl, andZ1 is CX3, and X2 is H and X1 and X3 are independently halogen or H, andeach R3 is independently H, C1-C6alkyl or C1-C6alkoxy.

In another embodiment, the compound of Formula I is a compound ofFormula Ib

wherein A, X1, X2, W, Z1, R1, R2, R3, R4, n, p, and q are describedabove.

In one embodiment of Formula Ib, A is methyl.

In one embodiment of Formula Ib, A is ethyl.

In one embodiment of Formula Ib, A is branched C3-C8alkyl.

In one embodiment of Formula Ib, A is isopropyl.

In one embodiment of Formula Ib, A is tert-butyl.

In one embodiment of Formula Ib, A is fluoroC1-C6alkyl wherein the alkylis fully or partially fluorinated.

In one embodiment of Formula Ib, A is C3-C8carbocyclyl.

In one embodiment of Formula Ib, A is cyclopropyl.

In one embodiment of Formula Ib, A is cyclobutyl.

In one embodiment of Formula Ib, A is cyclopentyl.

In one embodiment of Formula Ib, A is cyclohexyl.

In one embodiment of Formula Ib, A is a 4-8 membered heterocyclic ring.

In one embodiment of Formula Ib, A is a oxetanyl.

In one embodiment of Formula Ib, A is a tetrahydrofuranyl.

In one embodiment of Formula Ib, A is tetrahydropyranyl.

In one embodiment of Formula Ib, W is C5-C6heteroaryl optionallysubstituted by one, two, or three R5.

In one embodiment of Formula Ib, W is pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, thiazolyl, triazolyl, pyridinyl and wherein each W isoptionally substituted by one, two, or three R5.

In one embodiment of Formula Ib, W is pyrazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ib, W is imidazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ib, W is isoxazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ib, W is oxazolyl optionally substituted byone or two R5.

In one embodiment of Formula Ib, W is thiazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ib, W is triazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ib, W is pyridinyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ib, W is —NHC(O)R6, —NHC(O)R7, or—NHC(O)N(R8)R9.

In one embodiment of Formula Ib, W is —NHC(O)R6.

In one embodiment of Formula Ib, W is —NHC(O)R7.

In one embodiment of Formula Ib, W is —NHC(O)N(R8)R9.

In one embodiment of Formula Ib, W is —C(O)R11.

In one embodiment of Formula Ib, W is phenyl optionally substituted byone, two, or three R5.

In one embodiment of Formula Ib, Z1 is N, and X1 and X2 are individuallyand independently hydrogen, C1-C6 alkyl, halogen or fluoro-C1-C6 alkylwherein the alkyl chain is partially or completely fluorinated.

In one embodiment of Formula Ib, Z1 is N, and X1 and X2 are individuallyand independently hydrogen or C1-C6 alkyl.

In one embodiment of Formula Ib, Z1 is N, and X1 and X2 are hydrogen.

In one embodiment of Formula Ib, Z1 is N, and one of X1 and X2 ishydrogen and the other is C1-C6alkyl.

In one embodiment of Formula Ib, Z1 is CX3, and X1 and X2 and X3 areindividually and independently hydrogen, C1-C6 alkyl, halogen orfluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated.

In one embodiment of Formula Ib, Z1 is CX3, and X1 and X2 and X3 areindividually and independently hydrogen or halogen.

In one embodiment of Formula Ib, Z1 is CX3, and X1 and X3 are halogen,and X2 is hydrogen.

In one embodiment of Formula Ib, R1 and R2 are individually andindependently H, C1-C6 alkyl, or fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated.

In one embodiment of Formula Ib, R1 and R2 are H.

In one embodiment of Formula Ib, R1 and R2 are C1-C6alkyl.

In one embodiment of Formula Ib, R1 is H and R2 is C1-C6alkyl.

In one embodiment of Formula Ib, R3 is H, halogen, C1-C6 alkyl,fluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated, branched C3-C8 alkyl, C3-C8 cycloalkyl, C1-C6 alkoxy,fluoro-C1-C6 alkoxy wherein the alkyl chain is partially or completelyfluorinated, branched C3-C6 alkoxy, hydroxyl, or cyano.

In one embodiment of Formula Ib, R3 is H.

In one embodiment of Formula Ib, R3 is C1-C6 alkoxy.

In one embodiment of Formula Ib, R3 is fluoro-C1-C6 alkoxy wherein thealkyl chain is partially or completely fluorinated.

In one embodiment of Formula Ib, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and q is 0 or 1, and W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is N, and X1 is H, and X2 is C1-C6alkyl, and R3 is Hor C1-C6alkoxy.

In one embodiment of Formula Ib, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and q is 0 or 1, and W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is N, and X2 is H, and X1 is C1-C6alkyl, and R3 is Hor C1-C6alkoxy.

In one embodiment of Formula Ib, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and q is 0 or 1, and W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is N, and X1 and X2 are H, and R3 is H or C1-C6alkoxy.

In one embodiment of Formula Ib, A is C1-C6 alkyl, branched C3-C8alkyl,or C3-C8carbocyclyl, and q is 0 or 1, and W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is CX3, and X2 is H and X1 and X3 are independentlyhalogen or H, and R3 is H or C1-C6alkoxy.

In another embodiment, the compound of Formula I is a compound ofFormula Ic:

wherein X1, X2, W, Z1, R3, R4, n, and p are described above.

In one embodiment of Formula Ic, W is pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W isoptionally substituted by one, two, or three R5.

In one embodiment of Formula Ic, W is pyrazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ic, W is imidazolyl optionally substitutedby one, two, or three R5.

In one embodiment Formula Ic, W is isoxazolyl optionally substituted byone or two R5.

In one embodiment of Formula Ic, W is oxazolyl optionally substituted byone or two R5.

In one embodiment of Formula Ic, W is thiazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Ic, W is triazolyl optionally substitutedby one or two R5; or a pharmaceutically acceptable salt, enantiomer,stereoisomer, or tautomer thereof

In one embodiment of Formula Ic, W is pyridinyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Ic, W is —NHC(O)R6, —NHC(O)R7, or—NHC(O)N(R8)R9.

In one embodiment of Formula Ic W is —NHC(O)R6.

In one embodiment of Formula Ic, W is —NHC(O)R7.

In one embodiment of Formula Ic, W is —NHC(O)N(R8)R9.

In one embodiment of Formula Ic, W is —C(O)R11.

In one embodiment of Formula Ic, W is phenyl optionally substituted byone, two, or three R5.

In one embodiment of Formula Ic, Z1 is N, and X1 and X2 are individuallyand independently hydrogen, C1-C6 alkyl, halogen or fluoro-C1-C6 alkylwherein the alkyl chain is partially or completely fluorinated.

In one embodiment of Formula Ic, Z1 is N, and X1 and X2 are individuallyand independently hydrogen or C1-C6 alkyl.

In one embodiment of Formula Ic, Z1 is N, and X1 and X2 are hydrogen.

In one embodiment of Formula Ic, Z1 is N, and one of X1 and X2 ishydrogen and the other is C1-C6alkyl.

In one embodiment of Formula Ic, Z1 is CX3, and X1 and X2 and X3 areindividually and independently hydrogen, C1-C6 alkyl, halogen orfluoro-C1-C6 alkyl wherein the alkyl chain is partially or completelyfluorinated.

In one embodiment of Formula Ic, Z1 is CX3, and X1 and X2 and X3 areindividually and independently hydrogen or halogen.

In one embodiment of Formula Ic, Z1 is CX3, and X1 and X3 are halogen,and X2 is hydrogen.

In one embodiment of Formula Ic, W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is N, and X1 is H, and X2 is C1-C6alkyl, and R3 is Hor C1-C6alkyl.

In one embodiment of Formula Ic, W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is N, and X2 is H, and X1 is C1-C6alkyl, and R3 is Hor C1-C6alkyl.

In one embodiment of Formula Ic, W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is N, and X1 and X2 are H, and R3 is H or C1-C6alkyl.

In one embodiment of Formula Ic, W is pyrazolyl, imidazolyl, orpyridinyl, and Z1 is CX3, and X2 is H and X1 and X3 are independentlyhalogen or H, and R3 is H or C1-C6alkyl.

In another embodiment, the compound of Formula I is a compound ofFormula Id:

wherein A, X1, X2, W, R3, R4, n, and p are described above.

In one embodiment of Formula Id, A is methyl and R3 is H.

In one embodiment of Formula Id, A is ethyl.

In one embodiment of Formula Id, A is branched C3-C8alkyl.

In one embodiment of Formula Id, A is isopropyl.

In one embodiment of Formula Id, A is tert-butyl.

In one embodiment of Formula Id, A is fluoroC1-C6alkyl wherein the alkylis fully or partially fluorinated.

In one embodiment of Formula Id, A is 2,2,2-trifluoroethyl.

In one embodiment of Formula Id, A is C3-C8carbocyclyl.

In one embodiment of Formula Id, A is cyclopropyl.

In one embodiment of Formula Id A is cyclobutyl.

In one embodiment of Formula Id, A is cyclopentyl.

In one embodiment of Formula Id, A is cyclohexyl.

In one embodiment of Formula Id, A is a 4-8 membered heterocyclic ring.

In one embodiment of Formula Id, A is a oxetanyl.

In one embodiment of Formula Id, A is a tetrahydrofuranyl.

In one embodiment of Formula Id, A is a tetrahydropyranyl.

In one embodiment of Formula Id, W is C5-C6heteroaryl optionallysubstituted by one, two, or three R5.

In one embodiment of Formula Id, W is pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, thiazolyl, triazolyl, or pyridinyl and wherein each W isoptionally substituted by one, two, or three R5.

In one embodiment of Formula Id, W is pyrazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Id, W is imidazolyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Id, W is isoxazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Id, W is oxazolyl optionally substituted byone or two R5.

In one embodiment of Formula Id, W is thiazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Id, W is triazolyl optionally substitutedby one or two R5.

In one embodiment of Formula Id, W is pyridinyl optionally substitutedby one, two, or three R5.

In one embodiment of Formula Id, W is —NHC(O)R6, —NHC(O)R7, or—NHC(O)N(R8)R9.

In one embodiment of Formula Id, W is —NHC(O)R6.

In one embodiment of Formula Id, W is —NHC(O)R7.

In one embodiment of Formula Id, W is —NHC(O)N(R8)R9.

In one embodiment of Formula Id, W is —C(O)R11.

In one embodiment of Formula Id, W is phenyl optionally substituted byone, two, or three R5.

In one embodiment of Formula Id, X1 and X2 are individually andindependently hydrogen, C1-C6 alkyl, halogen or fluoro-C1-C6 alkylwherein the alkyl chain is partially or completely fluorinated.

In one embodiment of Formula Id, X1 and X2 are hydrogen.

In some embodiments, the invention comprises a compound selected fromthe group consisting ofN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,2-oxo-3-(tetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)imidazolidine-1-carboxamide,N-(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclohexyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-(1-methoxycyclopropyl)ethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide,3-cyclohexyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-(3-methoxy-3-methylbutyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(4,4-difluorocyclohexyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(4,4-difluorocyclohexyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,(R)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopentyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclohexyl-4,4-dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclohexyl-4,4-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)—N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,4-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(cyanomethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopentyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-methyl-N-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-ethyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,4-((6-(3-(tert-butyl)-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide,N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-(1-methoxycyclopropyl)ethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxypropyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(1-methoxypropan-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclohexyl-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxy-3-methylbutyl)-2-oxoimidazolidine-1-carboxamide,N-(5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4,4-difluorocyclohexyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclopentyl-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide,N-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-4-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,4-((6-(3-ethyl-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide,N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,andN-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide.

In certain embodiments, the invention comprises a method of treatingmammalian disease at least partially mediated by the kinase activity ofc-FMS, PDGFR-b, or c-KIT kinases, wherein the kinase is a wildtype form,a mutant oncogenic form, an aberrant fusion protein form or a polymorphthereof. The method comprises administering to a mammal in need thereofan effective amount of a compound of Formula I as described herein.

In other embodiments, the present invention comprises a pharmaceuticalcomposition, comprising a compound of Formula I and a pharmaceuticallyacceptable carrier.

In certain embodiments, the composition comprises an additive selectedfrom adjuvants, excipients, diluents, or stabilizers.

In some embodiments, the invention includes a method of treating cancer,gastrointestinal stromal tumors, hyperproliferative diseases, metabolicdiseases, neurodegenerative diseases, solid tumors, melanomas,glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas,multiple myelomas, cervical carcinomas, metastasis of primary tumorsites, cancers that are metastatic to bone, papillary thyroid carcinoma,non-small cell lung cancer, colonic cancers, rheumatoid arthritis,osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn'sdisease, asthma, chronic obstructive pulmonary disease, osteoporosis,mastocytosis, or mast cell leukemia, the method comprising administeringto a patient in need thereof an effective amount of a compound ofFormula I.

In some embodiments, the invention includes a method of treatingglioblastomas, breast cancers, pancreatic cancers, metastasis of primarytumor sites, or cancers that are metastatic to bone, the methodcomprising administering to a patient in need thereof an effectiveamount of a compound of Formula I.

In certain embodiments of the present methods, the compound isadministered orally, parenterally, by inhalation, or subcutaneously.

In some embodiments, the invention provides the use of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, in thetreatment of cancer, gastrointestinal stromal tumors, hyperproliferativediseases, metabolic diseases, neurodegenerative diseases, solid tumors,melanomas, glioblastomas, ovarian cancer, pancreatic cancer, prostatecancer, lung cancers, breast cancers, renal cancers, hepatic cancers,osteosarcomas, multiple myelomas, cervical carcinomas, metastasis ofprimary tumor sites, cancers that are metastatic to bone, papillarythyroid carcinoma, non-small cell lung cancer, colonic cancers,rheumatoid arthritis, osteoarthritis, multiple sclerosis, autoimmunenephritis, lupus, Crohn's disease, asthma, chronic obstructive pulmonarydisease, osteoporosis, mastocytosis, or mast cell leukemia, the methodcomprising administering to a patient in need thereof an effectiveamount of a compound of Formula I.

In some embodiments, the invention provides the use of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, in thetreatment of glioblastomas, breast cancers, pancreatic cancers,metastasis of primary tumor sites, or cancers that are metastatic tobone, the method comprising administering to a patient in need thereofan effective amount of a compound of Formula I.

In some embodiments, the invention provides for the use of a compound ofFormula I, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of cancer,gastrointestinal stromal tumors, hyperproliferative diseases, metabolicdiseases, neurodegenerative diseases, solid tumors, melanomas,glioblastomas, ovarian cancer, pancreatic cancer, prostate cancer, lungcancers, breast cancers, renal cancers, hepatic cancers, osteosarcomas,multiple myelomas, cervical carcinomas, metastasis of primary tumorsites, cancers that are metastatic to bone, papillary thyroid carcinoma,non-small cell lung cancer, colonic cancers, rheumatoid arthritis,osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn'sdisease, asthma, chronic obstructive pulmonary disease, osteoporosis,mastocytosis, or mast cell leukemia.

In certain embodiments, the invention provides for the use of a compoundof Formula I, or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament for the treatment of glioblastomas, breastcancers, pancreatic cancers, metastasis of primary tumor sites, orcancers that are metastatic to bone.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs.

Throughout this disclosure, various patents, patent applications andpublications are referenced. The disclosures of these patents, patentapplications and publications in their entireties are incorporated intothis disclosure by reference in order to more fully describe the stateof the art as known to those skilled therein as of the date of thisdisclosure. This disclosure will govern in the instance that there isany inconsistency between the patents, patent applications andpublications and this disclosure.

For convenience, certain terms employed in the specification, examplesand claims are collected here. Unless defined otherwise, all technicaland scientific terms used in this disclosure have the same meanings ascommonly understood by one of ordinary skill in the art to which thisdisclosure belongs. The initial definition provided for a group or termprovided in this disclosure applies to that group or term throughout thepresent disclosure individually or as part of another group, unlessotherwise indicated.

The compounds of this disclosure include any and all possible isomers,stereoisomers, enantiomers, diastereomers, tautomers, andpharmaceutically acceptable salts. Thus, the terms “compound”,“compounds”, “test compound” or “test compounds” as used in thisdisclosure refer to the compounds of this disclosure and any and allpossible isomers, stereoisomers, enantiomers, diastereomers, tautomers,and pharmaceutically acceptable salts thereof.

DEFINITIONS

The term “alkyl” as used herein refers to a straight chain alkyl,wherein alkyl chain length is indicated by a range of numbers. Inexemplary embodiments, “alkyl” refers to an alkyl chain as defined abovecontaining 1, 2, 3, 4, 5, or 6 carbons (i.e., C1-C6 alkyl). Examples ofan alkyl group include, but are not limited to, methyl, ethyl, propyl,butyl, pentyl, and hexyl.

The term “branched alkyl” as used herein refers to an alkyl chainwherein a branching point in the chain exists, and the total number ofcarbons in the chain is indicated by a range of numbers. In exemplaryembodiments, “branched alkyl” refers to an alkyl chain as defined abovecontaining from 3, 4, 5, 6, 7, or 8 carbons (i.e., branched C3-C8alkyl). Examples of a branched alkyl group include, but are not limitedto, iso-propyl, iso-butyl, secondary-butyl, and tertiary-butyl,2-pentyl, 3-pentyl, 2-hexyl, and 3-hexyl.

The term “alkoxy” as used herein refers to —O-(alkyl), wherein “alkyl”is as defined above.

The term “branched alkoxy” as used herein refers to —O-(branched alkyl),wherein “branched alkyl” is as defined above.

The term “alkylene” as used herein refers to an alkyl moiety interposedbetween two other atoms. In exemplary embodiments, “alkylene” refers toan alkyl moiety as defined above containing 1, 2, or 3 carbons. Examplesof an alkylene group include, but are not limited to —CH₂—, —CH₂CH₂—,and —CH₂CH₂CH₂—. In exemplary embodiments, alkylene groups are branched.

The term “alkynyl” as used herein refers to a carbon chain containingone carbon-carbon triple bond. In exemplary embodiments, “alkynyl”refers to a carbon chain as described above containing 2 or 3 carbons(i.e., C2-C3 alkynyl). Examples of an alkynyl group include, but are notlimited to, ethyne and propyne.

The term “aryl” as used herein refers to a cyclic hydrocarbon, where thering is characterized by delocalized π electrons (aromaticity) sharedamong the ring members, and wherein the number of ring atoms isindicated by a range of numbers. In exemplary embodiments, “aryl” refersto a cyclic hydrocarbon as described above containing 6, 7, 8, 9, or 10ring atoms (i.e., C6-C10 aryl). Examples of an aryl group include, butare not limited to, benzene, naphthalene, tetralin, indene, and indane.

The term “cycloalkyl” as used herein refers to a monocyclic saturatedcarbon ring, wherein the number of ring atoms is indicated by a range ofnumbers. In exemplary embodiments, “cycloalkyl” refers to a carbon ringas defined above containing 3, 4, 5, 6, 7, or 8 ring atoms (i.e., C3-C8cycloalkyl). Examples of a cycloalkyl group include, but are not limitedto, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, andcyclooctyl.

The term “halogen” or “halo” as used herein refers to fluorine,chlorine, bromine, and iodine.

The term “heterocycle” or “heterocyclyl” as used herein refers to acyclic hydrocarbon, wherein at least one of the ring atoms is an O, N,or S, wherein the number of ring atoms is indicated by a range ofnumbers. Heterocyclyl moieties as defined herein have C or N bondinghands through which the heterocyclyl ring is connected to an adjacentmoiety. For example, in some embodiments, a ring N atom from theheterocyclyl is the bonding atom of the heterocylic moiety. In exemplaryembodiments, “heterocyclyl” refers to a monocyclic hydrocarboncontaining 4, 5, 6, 7 or 8 ring atoms (i.e., C4-C8 heterocyclyl).Examples of a heterocycle group include, but are not limited to,aziridine, oxirane, thiirane, azetidine, oxetane, thietane, pyrrolidine,tetrahydrofuran, pyran, thiopyran, thiomorpholine, thiomorpholineS-oxide, thiomorpholine S-dioxide, oxazoline, tetrahydrothiophene,piperidine, tetrahydropyran, thiane, imidazolidine, oxazolidine,thiazolidine, dioxolane, dithiolane, piperazine, oxazine, dithiane, anddioxane.

The term “heteroaryl” as used herein refers to a cyclic hydrocarbon,where at least one of the ring atoms is an O, N, or S, the ring ischaracterized by delocalized π electrons (aromaticity) shared among thering members, and wherein the number of ring atoms is indicated by arange of numbers. Heteroaryl moieties as defined herein have C or Nbonding hands through which the heteroaryl ring is connected to anadjacent moiety. For example, in some embodiments, a ring N atom fromthe heteroaryl is the bonding atom of the heteroaryl moiety. Inexemplary embodiments, “heteroaryl” refers to a cyclic hydrocarbon asdescribed above containing 5 or 6 ring atoms (i.e., C5-C6 heteroaryl).Examples of a heteroaryl group include, but are not limited to, pyrrole,furan, thiene, oxazole, thiazole, isoxazole, isothiazole, imidazole,pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, pyridine,pyrimidine, pyrazine, pyridazine, and triazine.

The term “substituted” in connection with a moiety as used herein refersto a further substituent which is attached to the moiety at anyacceptable location on the moiety. Unless otherwise indicated, moietiescan bond through a carbon, nitrogen, oxygen, sulfur, or any otheracceptable atom.

The term “salts” as used herein embraces pharmaceutically acceptablesalts commonly used to form alkali metal salts of free acids and to formaddition salts of free bases. The nature of the salt is not critical,provided that it is pharmaceutically acceptable. Suitablepharmaceutically acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Exemplary pharmaceutical saltsare disclosed in Stahl, P. H., Wermuth, C. G., Eds. Handbook ofPharmaceutical Salts: Properties, Selection and Use; Verlag HelveticaChimica Acta/Wiley-VCH: Zurich, 2002, the contents of which are herebyincorporated by reference in their entirety. Specific non-limitingexamples of inorganic acids are hydrochloric, hydrobromic, hydroiodic,nitric, carbonic, sulfuric and phosphoric acid. Appropriate organicacids include, without limitation, aliphatic, cycloaliphatic, aromatic,arylaliphatic, and heterocyclyl containing carboxylic acids and sulfonicacids, for example formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic(pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, 3-hydroxybutyric, galactaric orgalacturonic acid. Suitable pharmaceutically acceptable salts of freeacid-containing compounds disclosed herein include, without limitation,metallic salts and organic salts. Exemplary metallic salts include, butare not limited to, appropriate alkali metal (group Ia) salts, alkalineearth metal (group IIa) salts, and other physiological acceptablemetals. Such salts can be made from aluminum, calcium, lithium,magnesium, potassium, sodium and zinc. Exemplary organic salts can bemade from primary amines, secondary amines, tertiary amines andquaternary ammonium salts, for example, tromethamine, diethylamine,tetra-N-methylammonium, N,N′-dibenzylethylenediamine, chloroprocaine,choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine)and procaine.

The terms “administer,” “administering, or “administration” as usedherein refer to either directly administering a compound orpharmaceutically acceptable salt of the compound or a composition to asubject.

The term “carrier” as used herein encompasses carriers, excipients, anddiluents, meaning a material, composition or vehicle, such as a liquidor solid filler, diluent, excipient, solvent or encapsulating materialinvolved in carrying or transporting a pharmaceutical agent from oneorgan, or portion of the body, to another organ or portion of the body.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The terms “effective amount” and “therapeutically effective amount” areused interchangeably in this disclosure and refer to an amount of acompound that, when administered to a subject, is capable of reducing asymptom of a disorder in a subject. The actual amount which comprisesthe “effective amount” or “therapeutically effective amount” will varydepending on a number of conditions including, but not limited to, theparticular disorder being treated, the severity of the disorder, thesize and health of the patient, and the route of administration. Askilled medical practitioner can readily determine the appropriateamount using methods known in the medical arts.

The terms “isolated” and “purified” as used herein refer to a componentseparated from other components of a reaction mixture or a naturalsource. In certain embodiments, the isolate contains at least about 50%,at least about 55%, at least about 60%, at least about 65%, at leastabout 70%, at least about 75%, at least about 80%, at least about 85%,at least about 90%, at least about 95%, or at least about 98% of thecompound or pharmaceutically acceptable salt of the compound by weightof the isolate.

The phrase “pharmaceutically acceptable” as used herein refers to thosecompounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used in this disclosure, the terms “patient” or “subject” include,without limitation, a human or an animal Exemplary animals include, butare not limited to, mammals such as mouse, rat, guinea pig, dog, feline,horse, cow, pig, monkey, chimpanzee, baboon, or rhesus monkey.

The terms “treatment,” “treat,” and “treating,” are meant to include thefull spectrum of intervention for the cancer from which the patient issuffering, such as administration of the active compound to alleviate,slow or reverse one or more of the symptoms and to delay progression ofthe cancer even if the cancer is not actually eliminated. Treating canbe curing, improving, or at least partially ameliorating the disorder.

Structural, chemical and stereochemical definitions are broadly takenfrom IUPAC recommendations, and more specifically from Glossary of Termsused in Physical Organic Chemistry (IUPAC Recommendations 1994) assummarized by Müller, P. Pure Appl. Chem. 1994, 66, pp. 1077-1184 andBasic Terminology of Stereochemistry (IUPAC Recommendations 1996) assummarized by Moss, G. P. Pure Appl. Chem. 1996, 68, pp. 2193-2222.

Atropisomers are defined as a subclass of conformers which can beisolated as separate chemical species and which arise from restrictedrotation about a single bond.

Regioisomers or structural isomers are defined as isomers involving thesame atoms in different arrangements.

Enantiomers are defined as one of a pair of molecular entities which aremirror images of each other and non-superimposable.

Diastereomers or diastereoisomers are defined as stereoisomers otherthan enantiomers. Diastereomers or diastereoisomers are stereoisomersnot related as mirror images. Diastereoisomers are characterized bydifferences in physical properties, and by some differences in chemicalbehavior towards achiral as well as chiral reagents.

The term “tautomer” as used herein refers to compounds produced by thephenomenon wherein a proton of one atom of a molecule shifts to anotheratom. See March, Advanced Organic Chemistry: Reactions, Mechanisms andStructures, 4^(th) Ed., John Wiley & Sons, pp. 69-74 (1992). Tautomerismis defined as isomerism of the general form

G-X—YλZ

X═Y—Z-G

where the isomers (called tautomers) are readily interconvertible; theatoms connecting the groups X, Y and Z are typically any of C, H, O, orS, and G is a group which becomes an electrofuge or nucleofuge duringisomerization. The most common case, when the electrofuge is H⁺, is alsoknown as “prototropy.” Tautomers are defined as isomers that arise fromtautomerism, independent of whether the isomers are isolable.

The exemplified compounds of the present invention are preferablyformulated as a pharmaceutical composition using a pharmaceuticallyacceptable carrier and administered by a variety of routes. Preferably,such compositions are for oral administration. Such pharmaceuticalcompositions and processes for preparing them are well known in the art.See, e.g., REMINGTON: THE SCIENCE AND PRACTICE OF PHARMACY (A. Gennaro,et al., eds., 19^(th) ed., Mack Publishing Co., 1995).

The compounds of Formula I, or pharmaceutically acceptable saltsthereof, may be prepared by a variety of procedures known in the art, aswell as those described below. The specific synthetic steps may becombined in different ways to prepare the Formula I compounds, or apharmaceutically acceptable salt thereof

The compounds employed as initial starting materials in the synthesis ofthe compounds of Formula Ia are well known and, to the extent notcommercially available, are readily synthesized using specificreferences provided, by standard procedures commonly employed by thoseof ordinary skill in the art, or are found in general reference texts.

Examples of known procedures and methods include those described ingeneral reference texts such as Comprehensive Organic Transformations,VCH Publishers Inc, 1989; Compendium of Organic Synthetic Methods,Volumes 1-10, 1974-2002, Wiley Interscience; Advanced Organic Chemistry,Reactions Mechanisms, and Structure, 5^(th) Edition, Michael B. Smithand Jerry March, Wiley Interscience, 2001; Advanced Organic Chemistry,4^(th) Edition, Part B, Reactions and Synthesis, Francis A. Carey andRichard J. Sundberg, Kluwer Academic/Plenum Publishers, 2000, etc., andreferences cited therein.

ChemDraw version 10 or 12 (CambridgeSoft Corporation, Cambridge, Mass.)was used to name the structures of intermediates and exemplifiedcompounds.

The following abbreviations are used in this disclosure and have thefollowing definitions: “ADP” is adenosine diphosphate “conc.” isconcentrated, “DBU” is 1,8-diazabicyclo[5.4.0]undec-7-ene, “DCM” isdichloromethane, “DIEA” is N,N-diisopropylethylamine, “DMA” isN,N-dimethylacetamide, “DMAP” is 4-(dimethylamino)pyridine, “DMF” isN,N-dimethylformamide, “dppf” is 1,1′-bis(diphenylphosphino)ferrocene,“DMEM” is Dulbecco's Modified Eagle Media, “DMSO” is dimethylsulfoxide,“DPPA” is diphenylphosphryl azide, “ESI” is electrospray ionization,“Et₂O” is diethylether, “EtOAc” is ethyl acetate, “EtOH” is ethanol,“GST” is glutathione S-transferase, “h” is hour or hours, “Hex” ishexane, “IC₅₀” is half maximal inhibitory concentration, “LiMHDS” islithium bis(trimethylsilyl)amide, “MeCN” is acetonitrile, “MeOH” ismethanol, “Me₄tBuXPhos” isdi-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine,“MHz” is megahertz, “min” is minute or minutes, “MS” is massspectrometry, “MTBE” is methyl tert-butyl ether, “NADH” is nicotinamideadenine dinucleotide, “NBS” is N-bromosuccinimide, “NMR” is nuclearmagnetic resonance, “PBS” is phosphate buffered saline, “Pd/C” ispalladium on carbon, “Pd₂(dba)₃” istris(dibenzylideneacetone)dipalladium(0), “Pd(PPh₃)₄” istetrakis(triphenylphosphine)palladium (0), “prep-HPLC” is preparativehigh performance liquid chromatography, “RT” is room temperature whichis also known as “ambient temp,” which will be understood to consist ofa range of normal laboratory temperatures ranging from 15-25° C.,“satd.” is saturated, “TEA” is triethylamine, “TFA” is trifluoroaceticacid, “THF” is tetrahydrofuran, “Tris” istris(hydroxymethyl)aminomethane, “Xantphos” is4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and “X-Phos” is2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl.

General Chemistry

The compounds of Formula I are prepared by the general synthetic methodsillustrated in the schemes below and the accompanying examples. Suitablereaction conditions for the steps of these schemes are well known in theart and appropriate substitutions of solvents and co-reagents are withinthe skill of the art. Those skilled in the art will understand thatsynthetic intermediates may be isolated and/or purified by well knowntechniques as needed or desired, and that it will be possible to usevarious intermediates directly in subsequent synthetic steps with littleor no purification. Furthermore, those skilled in the art willappreciate that in some instances, the order in which moieties areintroduced is not critical. The particular order of steps required toproduce the compounds of Formula I is dependent upon the particularcompound being synthesized, the starting compound, and the relativelability of the substituted moieties, as is well appreciated by theordinary skilled chemist. All substituents, unless otherwise indicated,are as defined above.

The compounds of Formula I may contain —NH or —OH moieties in the W, R1,R2, R3, R5, R6, R7, R8 and R9 positions. It will be understood by thoseskilled in the art that in some instances it may be advantageous to usean amine protecting group during synthesis to temporarily mask one ormore —NH moieties. Said protecting group can be removed from anysubsequent intermediate leading to the synthesis of compound 1, usingstandard conditions that effect removal of said protecting group, saidconditions of which will be familiar to those skilled in the art. Whennot specified in a scheme, it will be understood that the W, R1, R2, R3,R5, R6, R7, R8 and R9 moieties represented in the schemes below mayoptionally contain standard amino or hydroxyl protecting groups that canbe removed at any opportune time in the synthetic sequence.

Compounds 1 of the invention can be prepared as illustrated in Scheme 1.In one embodiment, cyclic ureas of formula 2 are reacted with phosgene(or an equivalent, such as diphosgene or triphosgene) in the presence ofa base, for example pyridine, to provide an intermediate carbonylchloride 3. Intermediate 3 may be isolated or may be generated and usedin situ. Further reaction of carbonyl chloride 3 with general amine 4 inthe presence of a base such as pyridine or triethylamine providescompounds of formula I. In another embodiment, intermediate 3 is reactedwith amine 5 to provide intermediate 6. Further conversion of 6 to 1 iseffected by reaction of 6 with reagent M-W (7), wherein M is H (when Wis —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9, or an N-linked heteroaryl), oralternately (when W is heteroaryl) wherein M is trialkylstanyl or aboronic acid or boronate ester. Conditions for the transformation of 6to 1 are dependent on the nature of the W-moiety, but generally includethe use of palladium catalysts, for example Pd(PPh₃)₄ or Pd₂(dba)₃,optionally in the presence of additional ligands, for example Xantphos.General conditions to accomplish these transformation (including Suzukicoupling, Stille coupling, Buchwald amidation) are well known to thoseskilled in the art.

Alternately, compounds of Formula 1 can be prepared directly fromintermediate 10 by N-alkylation with an appropriate alkylating agent. Inone embodiment, the alkylating agent is intermediate 12 wherein Y is ahalide or a sulfonate, for example a mesylate, triflate or tosylate.Similarly, intermediate 6 can also be prepared by alkylation of 11 with12. In another embodiment, the alkylating agent is an A-substitutedoxirane. Intermediates 10 and 11 can be prepared by reaction of 9 with 4or 5 respectively, as described above for the reaction of 3 with 4 or 5.Intermediate 9 is in turn prepared from imidazolidin-2-one 8 bytreatment with phosgene or an equivalent such as triphosogene.

General amines 4 and 5 can be synthesized according to methods commonlyknown to those skilled in the art as illustrated in Schemes 2-4. Scheme2 illustrates the preparation of general amines 4 and 5. In oneembodiment, amine 5 can be prepared directly from the reaction of 13with dichloride 14. Suitable conditions include combining 13, 14 andpotassium tert-butoxide in a solvent, for example dimethylacetamide, andheating said mixture at a temp of 80-120° C. In another embodiment,amine 5 can be prepared from nitro compound 17 by reduction understandard conditions, for example by treatment with zinc dust in thepresence of ammonium chloride or by hydrogenation over Raney nickel.Nitro compound 17 is in turn prepared from the reaction of 16 withcompound 15, wherein Y is a halide. Suitable conditions to effect saidtransformation include combining 15 and 16 with a base, for examplepotassium carbonate, and heating said mixture at a temp of 80-120° C. ina solvent such as dimethylformamide to effect ether formation. Inanother embodiment, nitro 17 is obtained by the reaction of 18 withdichloride 14. In one embodiment, by analogy to Scheme 1, furtherconversion of 5 to 4 is effected by reaction of 5 with reagent M-W (7),wherein M is H (when W is —NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9, or anN-linked heteroaryl), or alternately (when W is heteroaryl) wherein M istrialkylstanyl or a boronic acid or boronate ester. Conditions for thetransformation of 5 to 4 are dependent on the nature of the W-moiety,but generally include the use of palladium catalysts, as furtherillustrated in the accompanying examples. In another embodiment,intermediate 17 can first be transformed to intermediate 19. Furtherreduction of the nitro group of 19 provides general amine 4.

Scheme 3 illustrates the synthesis of amine 24, a variant of generalamine 4 wherein W is isoxazol-5-yl. Reaction of amine 5 to withtrimethylsilylacetylene (20) in the presence of a palladium catalystaffords 21. Removal of the trimethylsilyl group affords 22. Conversionof 22 to isoxazole 24 is accomplished by [3+2] cycloaddition with thereagent derived from oxime 23, N-chlorosuccinimide, and triethylamine.Alternately, amine 24 can be prepared by reduction of the nitro moietyof 27, in turn available by a similar sequence of reactions commencingwith nitro-chloride 17.

Scheme 4 illustrates the synthesis of amine 31, a variant of generalamine 4 wherein W is —C(O)NR8(R9).

Scheme 5 illustrates an alternate preparation of general amine 38 (amine4 wherein Z1 is N and Z3 is CH) from iodide 33. Following Scheme 2,hydroxypyridine 33 and dichloride 14 are combined with heating in thepresence of a base such as potassium carbonate to provide iodo ether 34.Further reaction of 34 with an aminocarbonyl reagent 35, Cs₂CO₃ (2.115g, 6.46 mmol), X-Phos, and tris(dibenzylideneacetone)dipalladium[Pd₂(dba)₃] with heating in a suitable solvent, such as dioxane,provides 36. Suitable R-groups of 35 and 36 include alkyl or alkoxy.Using the methods described in Schemes 2 and 3, above, the chloride of36 can be converted to a W-moiety to provide 37. Removal of theRC(O)-protecting group of 37, for example by treatment with acid,provides amine 38, an example of general amine 4. In a similar manner,the RC(O)-protecting group of 36 can be directly removed to providegeneral intermediate 39, an example of general intermediate 5 wherein Z1is N and Z3 is CH.

General ureas of formula 2 useful for the invention can be prepared bythe general methods of Schemes 6-8. In one embodiment, urea 46 isprepared according to Scheme 6 commencing with isocyanate 40 (Y ishalo). Reaction of 40 with amine 41 provides urea 42. Treatment of 42with a base, for example sodium hydride, in an aprotic solvent, forexample THF, optionally while heating the reaction mixture, effects anintramolecular alkylation to form the cyclic urea 46. In someembodiments the conversion of 40 to 46 can be performed without theisolation of 42. In other embodiments, intermediate 42 can be preparedby reaction of amine 43 (Y is halo) with isocyanate 44. In otherembodiments, intermediate 42 can be prepared by reaction of amine 43 (Yis halo) with acid 45 in the presence of diphenylphosphoryl azide (DPPA)and heating said mixture to effect a Curtius rearrangement [in situgeneration of isocyanate 44]. It will be understood in Schemes 6 and 7that the R3 and R4 groups are independently variable within eachcompound and may also be hydrogen.

In another embodiment, urea 49 is prepared as shown in Scheme 7 by thereaction of allylic amine 47 with isocyanate 44 to provide 48. Treatmentof allylic urea 48 with an acid, for example trifluoroacetic acid,effects cyclization to form urea 49.

In another embodiment, urea 2 is prepared from imidazolidin-2-one 8 byalkylation with intermediate 12 wherein Y is a halide or a sulfonate(for example a mesylate, triflate or tosylate), as shown in Scheme 8.Conditions include the addition of a base, for example lithiumbis(trimethylsilyl)amide, optionally with heating.

Using the synthetic procedures and methods described herein and methodsknown to those skilled in the art, the following compounds were made:N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,2-oxo-3-(tetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)imidazolidine-1-carboxamide,N-(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclohexyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-(1-methoxycyclopropyl)ethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide,3-cyclohexyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-(3-methoxy-3-methylbutyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(4,4-difluorocyclohexyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(4,4-difluorocyclohexyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,(R)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopentyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclohexyl-4,4-dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclohexyl-4,4-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)—N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,4-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(cyanomethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopentyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-methyl-N-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-ethyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,4-((6-(3-(tert-butyl)-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide,N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-(1-methoxycyclopropyl)ethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxypropyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(1-methoxypropan-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclohexyl-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxy-3-methylbutyl)-2-oxoimidazolidine-1-carboxamide,N-(5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4,4-difluorocyclohexyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclopentyl-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide,N-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-4-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,4-((6-(3-ethyl-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide,N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,andN-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide.

EXAMPLES

The disclosure is further illustrated by the following examples, whichare not to be construed as limiting this disclosure in scope or spiritto the specific procedures herein described. It is to be understood thatthe examples are provided to illustrate certain embodiments and that nolimitation to the scope of the disclosure is intended thereby. It is tobe further understood that resort may be had to various otherembodiments, modifications, and equivalents thereof which may suggestthemselves to those skilled in the art without departing from the spiritof the present disclosure and/or scope of the appended claims.

Example A1

A solution of 5-bromo-2-nitropyridine (15 g, 73.9 mmol) in DMF (300 mL)was sparged with Ar, treated with Cs₂CO₃ (48.2 g, 148 mmol) and2-chloro-4-hydroxypyridine (10.53 g, 81 mmol), sparged again with Ar andheated at 85° C. overnight. The mixture was cooled to RT, filteredthrough a bed of silica gel, washed thoroughly with EtOAc, and thefiltrate treated with 5% LiCl and stirred overnight. The layers wereseparated, the aqueous layer extracted with additional EtOAc (4×) andthe combined organics were dried over Na₂SO₄ and concentrated todryness. The residue was dissolved in EtOAc, treated with 5% LiCl,stirred for 1 h, the layers separated and the aqueous layer extractedwith EtOAc (3×). The combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex). The material was suspended in MTBE, sonicated and theresulting solid collected via filtration to afford2-chloro-4-((6-nitropyridin-3-yl)oxy)pyridine (6.06 g, 33%). ¹H NMR (400MHz, DMSO-d₆): δ 8.62 (d, J=2.4, 1 H), 8.43-8.39 (m, 2H), 8.06 (dd,J=8.8, 2.8 Hz, 1H), 7.36 (d, J=2.0 Hz, 1H), 7.23 (dd, J=5.6, 2.0 Hz,1H); MS (ESI) m/z: 252.0 (M+H+).

Example A2

A suspension of Example A1 (14.38 g, 57.1 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(13.08 g, 62.9 mmol) and Cs₂CO₃ (55.9 g, 171 mmol) in DMF (150 mL) wassparged with Ar, treated with Pd(PPh₃)₄ (6.60 g, 5.71 mmol), spargedagain with Ar and heated at 90° C. overnight. The mixture was cooled toRT, the solids removed via filtration through diatomaceous earth, washedwith EtOAc and the filtrate concentrated to near-dryness. The residuewas treated with EtOAc, washed with 5% LiCl (1×) and the aqueous layerback-extracted with EtOAc (4×). The combined organics were dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford2-(1-methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (12.28g, 72%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.59 (d, J=2.8 Hz, 1H), 8.49 (d,J=5.6 Hz, 1H), 8.41 (d, J=8.9 Hz, 1H), 8.29 (s, 1H), 8.00 (d, J=0.7 Hz,1H), 7.97 (dd, J=8.9, 2.8 Hz, 1H), 7.44 (d, J=2.4 Hz, 1H), 6.97 (dd,J=5.6, 2.4 Hz, 1H), 3.85 (s, 3H); MS (ESI) m/z: 298.1 (M+H+).

A mixture of2-(1-methyl-1H-pyrazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (11.88g, 40.0 mmol) and NH₄Cl (22.4 g, 419 mmol) in EtOH (200 mL) and water(200 mL) was treated portion-wise with iron powder (22.4 g, 401 mmol),stirred for 0.5 h, treated with additional NH₄Cl (22.4 g, 419 mmol) andiron powder (22.4 g, 401 mmol) and stirred at RT for 3 h. The solidswere removed via filtration through diatomaceous earth and washed withEtOAc and DCM. The filtrate was washed with water, the aqueous layerback-extracted with DCM (4×) and the combined organics were dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (6.4 g,60%). MS (ESI) m/z: 268.1 (M+H+).

Example A3

A solution of 3-hydroxy-2-methylpyridine (20.0 g, 183 mmol) and Na₂CO₃(38.8 g, 367 mmol) in H₂O (320 mL) and MeOH (200 mL) was treated with I₂(46.5 g, 183 mmol) and stirred at RT for 1 h. The mixture was acidifiedwith HCl (2 M), extracted with EtOAc (2×) and the combined organics werewashed with brine, dried over Na₂SO₄ and concentrated to dryness. Thematerial was suspended in 1:1 EtOAc/Hex, sonicated and the solidcollected via filtration and dried. The filtrate was concentrated todryness, treated with DCM, the solid collected via filtration andcombined with the first solid to afford 6-iodo-2-methylpyridin-3-ol(20.5 g, 48%). MS (ESI) m/z: 236.0 (M+H⁺).

A mixture of 6-iodo-2-methylpyridin-3-ol (6.8 g, 28.9 mmol),2,4-dichloro pyridine (8.56 g, 57.9 mmol) and K₂CO₃ (4.00 g, 28.9 mmol)in DMA (50 mL) was heated at 110° C. for 16 h under argon. The mixturewas cooled to RT, treated with H₂O, extracted with EtOAc (2×) and thecombined organics were washed with H₂O, then brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to afford3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (7.35 g, 73%) as awhite solid. MS (ESI) m/z: 346.9 (M+H⁺).

A solution of 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (8.5g, 24.53 mmol) in dioxane (100 mL) was sparged with argon, treated withacetamide (5.07 g, 86 mmol), Cs₂CO₃ (11.99 g, 36.8 mmol), X-Phos (0.585g, 1.226 mmol) and Pd₂(dba)₃ (1.123 g, 1.226 mmol) and heated at 83° C.for 16 h. The mixture was cooled to RT, treated with EtOAc, solidsremoved via filtration through diatomaceous earth, rinsed well withEtOAc, and the filtrate washed with H₂O, then brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to affordN-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (3.8 g,56%) as an off-white solid. MS (ESI) m/z: 278.0 (M+H⁺).

Example A4

Method 1: A solution of Example A3 (3.83 g, 13.79 mmol) in dioxane (50mL) was sparged with argon, treated with a solution of K₂CO₃ (3.81 g,27.6 mmol) in H₂O (10 mL),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.44 g, 16.55 mmol) and Pd(PPh₃)₄ (0.637 g, 0.552 mmol) and heated at80° C. for 16 h. The mixture was cooled to RT, treated with H₂O,extracted with EtOAc (2×) and the combined organics washed with H₂O,then brine, dried over Na₂SO₄ and concentrated to dryness. The materialwas suspended in 3:2 EtOAc/Hex, sonicated and the resulting solidcollected via filtration and dried. The filtrate was concentrated todryness, purified via silica gel chromatography (MeOH/DCM) and combinedwith the isolated solid to affordN-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide(3.88 g, 87%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.60 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.01 (d, J=8.8 Hz, 1H), 7.95(s, 1H), 7.57 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.58 (dd,J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.25 (s, 3H), 2.08 (s, 3H); MS (ESI)m/z: 324.1 (M+H⁺).

A solution ofN-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide(3.88 g, 12.00 mmol) in THF (30 mL) was treated with 2M HCl (30 mL, 60mmol), heated at 65° C. for 6 h, cooled to RT and concentrated todryness. The mixture was treated with H₂O, neutralized with solidNaHCO₃, extracted with EtOAc (2×) and the combined organics were washedwith brine, dried over Na₂SO₄ and concentrated to dryness. The materialwas suspended in 3:2 EtOAc/Hex, sonicated and the resulting solidcollected via filtration and dried to afford6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(3.1 g, 92%) as a white solid. MS (ESI) m/z: 282.1 (M+H⁺).

Method 2: A mixture of Example A7 (4.42 g, 18.76 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(5.07 g, 24.38 mmol), and K₂CO₃ in dioxane (60 mL) and water (15 mL) wassparged with Ar, treated with Pd(PPh₃)₄ (1.084 g, 0.938 mmol), spargedwith Ar again and heated at 90° C. for 6 h. The reaction was cooled toRT, treated with saturated brine, and extracted with EtOAc (3×). Theorganics were dried over Na₂SO₄ and concentrated to dryness. The residuewas treated with EtOAc (30 mL) and briefly sonicated. The solids werecollected by filtration, washed with EtOAc (10 mL) and dried undervacuum to obtain the product (4.15 g, 79% yield) of suitable NMR purity.This material (4.15 g, 14.75 mmol) was dissolved in THF (300 mL) andMeOH (15 mL) and treated with thiol-modified silica gel (1.2 mmolthiol/g, 4.92 g, 5.90 mmol). The mixture was stirred at RT for 4 h,filtered through a pad of diatomaceous earth and washed with EtOAc (300mL) and THF (400 mL). The filtrate was concentrated to dryness. Theresidue was treated with EtOAc (30 mL) and the solid was collected byfiltration, washed with EtOAc and dried under vacuum at 80° C. to obtain5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (3.6 g,87% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.30 (d, J=5.7 Hz, 1H), 8.22(s, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.17 (d, J=8.7 Hz, 1H), 7.10 (d, J=2.4Hz, 1H), 6.49 (dd, J=5.7, 2.4 Hz, 1H), 6.34 (d, J=8.7 Hz, 1H), 5.93 (s,2H), 3.84 (s, 3H), 2.06 (s, 3H); MS (ESI) m/z: 282.1 (M+H⁺).

Example A5

A mixture of Example A1 (2.55 g, 10.13 mmol) and NH₄Cl (5.42 g, 101mmol) in THF (250 mL) and MeOH (250 mL) was treated with zinc dust (6.63g, 101 mmol), stirred at RT for 3 h, the solids removed via filtrationand the filtrate concentrated to dryness and purified by silica gelchromatography to provide 5-((2-chloropyridin-4-yl)oxy)pyridin-2-amine(1.41 g, 63% yield).

Example A6

A 0° C. solution of sulfuric acid (125 mL) was treated drop-wise withH₂O₂ (30%, 63.1 mL, 2058 mmol), stirred for 15 min, treated drop-wisewith a cold solution of 6-amino-3-bromo-2-picoline (35 g, 187 mmol) insulfuric acid (125 mL), allowed to warm to RT and stirred for 4 h. Themixture was poured onto ice (1.2 kg) and the resulting solid collectedvia filtration, dissolved in DCM, washed with brine, dried over Na₂SO₄and concentrated to dryness. The aqueous filtrate and washes werecombined, extracted with DCM (2×) and the combined organics were driedover Na₂SO₄, concentrated to dryness, purified via silica gelchromatography (EtOAc/Hex) and combined with the above-isolated solid toafford 3-bromo-2-methyl-6-nitropyridine (25.59 g, 63%). MS (ESI) m/z:218.9 (M+H⁺).

A solution of 3-bromo-2-methyl-6-nitropyridine (25.59 g, 118 mmol),K₂CO₃ (48.9 g, 354 mmol) and 2-chloro-4-hydroxy-pyridine (30.6 g, 236mmol) in DMF (160 mL) was sparged with Ar, heated at 100° C. overnight,then cooled to RT. The mixture was treated with water and EtOAc, thesolids removed via filtration through diatomaceous earth and washed withwater, EtOAc, then DCM. The aqueous filtrate was extracted with EtOAc(2×) and the organic extracts were combined with the organic filtrates,washed with water, then brine, dried over Na₂SO₄ and concentrated todryness. The residue was treated with MTBE, sonicated and the resultingsolid collected via filtration to afford3-((2-chloropyridin-4-yl)oxy)-2-methyl-6-nitropyridine (17.16 g, 55%).¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (d, J=5.7 Hz, 1H), 8.25 (d, J=8.7 Hz,1H), 7.95 (d, J=8.7 Hz, 1H), 7.29 (d, J=2.3 Hz, 1H), 7.16 (dd, J=5.7,2.3 Hz, 1H), 2.46 (s, 3H); MS (ESI) m/z: 266.0 (M+H⁺).

Example A7

Method A: Example A6 (5.0 g, 18.82 mmol) and ammonium chloride (30.2 g,565 mmol) were suspended in a mixture of MeOH:THF (1:1, 100 mL). Zinc(12.31 g, 188 mmol) was added portionwise over 10 min and then themixture was stirred at RT overnight. The reaction mixture was dilutedwith EtOAc (500 mL) and filtered. The filtrate was concentrated in vacuoand the residue was purified by silica gel chromatography to obtain5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-amine (3.72 g, 84%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.24 (d, J=5.7 Hz, 1H), 7.20 (d, J=8.7 Hz,1H), 6.89 (d, J=2.2 Hz, 1H), 6.85 (dd, J=5.8, 2.3 Hz, 1H), 6.35 (d,J=8.7 Hz, 1H), 6.02 (s, 2H), 2.05 (s, 3H); MS (ESI) m/z: 236.1 (M+H⁺).

Method B: A solution of Example A6 (1 g, 3.76 mmol) in EtOH (38 mL) wastreated with tin(II) chloride dihydrate (4.25 g, 18.8 mmol), heated at80° C. for 30 h, then cooled to RT and treated slowly with satd. NaHCO₃.The mixture was stirred for several minutes, the solids removed viafiltration through diatomaceous earth and the filtrate was dried overNa₂SO₄ and concentrated to dryness to afford crude5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-amine (645 mg, 73%)which was used without further purification. MS (ESI) m/z: 236.1 (M+H⁺).

Example A8

A 0° C. solution of 6-ethylpyridin-2-amine (3.37 g, 27.6 mmol) in CHCl3(30 mL) was treated portion-wise with NBS (4.91 g, 27.6 mmol) over 30min, stirred for 45 min, then concentrated to dryness. The residue wastreated with EtOAc (8 mL), filtered to remove solids and purified viasilica gel chromatography (EtOAc/Hex) to afford5-bromo-6-ethylpyridin-2-amine (3.79 g, 68%). ¹H NMR (400 MHz, DMSO-d₆):δ 7.43 (d, J=8.6 Hz, 1H), 6.21 (d, J=8.7 Hz, 1H), 6.03 (s, 2H), 2.61 (q,J=7.5 Hz, 2H), 1.11 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 201.0 (M+H⁺).

A 0° C. solution of H₂SO₄ (11 mL) was slowly treated with H₂O₂ (30%, 5.5mL), in an open flask, stirred for 5 min, treated drop-wise with asolution of 5-bromo-6-ethylpyridin-2-amine (3.79 g, 18.85 mmol) in H₂SO₄(10 mL) warmed to RT as the cooling bath expired and stirred overnight.The solution was poured into ice water (200 mL), treated with DCM,cooled to 0° C. and treated slowly with 50% NaOH until pH=10. The layerswere separated, the aqueous layer extracted with additional DCM (1×) andthe combined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford crude 3-bromo-2-ethyl-6-nitropyridine(3.168 g, 71%) which was used without further purification. ¹H NMR (400MHz, DMSO-d₆): δ 8.44 (d, J=8.5 Hz, 1H), 8.05 (d, J=8.5 Hz, 1H), 2.97(q, J=7.5 Hz, 2H), 1.24 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 231.0 (M+H⁺).

A mixture of 3-bromo-2-ethyl-6-nitropyridine (3.168 g, 13.71 mmol),2-chloro-4-hydroxypyridine (3.55 g, 27.4 mmol) and K₂CO₃ (5.69 g, 41.1mmol) in DMA (25 mL) was sparged with Ar and heated at 105° C.overnight. The mixture was cooled to RT, treated with EtOAc, washedsuccessively with 10% K₂CO₃, 5% LiCl, then brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to afford3-((2-chloropyridin-4-yl)oxy)-2-ethyl-6-nitropyridine (1.102 g, 28%). MS(ESI) m/z: 280.0 (M+H⁺).

Example A9

A mixture of Example A8 (1.10 g, 3.93 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.06 g, 5.11 mmol), K₂CO₃ (1.631 g, 11.80 mmol) and Pd(PPh₃)₄ (227 mg,0.197 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar andheated at 80° C. for 24 h. The mixture was cooled to RT, treated withEtOAc, washed with satd. NaHCO₃, then brine, dried over Na₂SO₄ andconcentrated to dryness to afford crude2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine(100% yield assumed) without further purification. MS (ESI) m/z: 326.1(M+H⁺).

A solution of crude2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine(1.280 g, 3.93 mmol) in MeOH (15 mL) and THF (15 mL) was treated withNH₄Cl (8.42 g, 157 mmol), cooled to 0° C., treated portion-wise withzinc dust (2.57 g, 39.3 mmol), warmed to RT as the cooling bath expiredand stirred overnight. The mixture was diluted with EtOAc, the solidsremoved via filtration through diatomaceous earth, washed with warm 2:1EtOAc/MeOH and the filtrate concentrated to dryness. The residue wastreated with EtOAc, heated to reflux, cooled to RT and the solidsremoved via filtration. The filtrate was again treated with EtOAc,heated to reflux and the solid collected via hot filtration. Thefiltrate was concentrated to dryness, purified via silica gelchromatography (MeOH/EtOAc) and combined with the above-isolated solidto afford6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(929 mg, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.30 (d, J=5.8 Hz, 1H), 8.22(s, 1H), 7.93 (s, 1H), 7.18 (d, J=8.7 Hz, 1H), 7.12 (d, J=2.4 Hz, 1H),6.51 (dd, J=5.7, 2.4 Hz, 1H), 6.36 (d, J=8.7 Hz, 1H), 5.97 (s, 2H),3.84-3.83 (m, 3H), 2.39 (q, J=7.6 Hz, 2H), 1.04 (t, J=7.5 Hz, 3H); MS(ESI) m/z: 296.1 (M+H⁺).

Example A10

A mixture of Example A7 (2.8 g, 11.88 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (3.38g, 15.45 mmol) and K₂CO₃ (3.28 g, 23.76 mmol) in dioxane 48 mL) andwater (12 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (1.373 g,1.188 mmol) and heated at 85° C. overnight. The mixture was cooled toRT, diluted with EtOAc, the solids removed via filtration throughdiatomaceous earth and the filtrate concentrated to dryness and purifiedvia silica gel chromatography (MeOH/DCM). The material was treated withMeCN, the solid collected via filtration and re-purified via silica gelchromatography (MeOH/DCM) to afford6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (3.08g, 89%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.56 (d, J=2.4 Hz, 1H), 8.96 (d,J=5.7 Hz, 1H), 8.71 (dd, J=8.1, 2.4 Hz, 1H), 7.86 (d, J=2.4 Hz, 1H),7.76 (d, J=8.1 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.18 (dd, J=5.7, 2.4 Hz,1H), 6.94 (dd, J=8.6, 0.7 Hz, 1H), 5.86 (s, 2H), 2.97 (s, 3H), 2.59 (s,3H); MS (ESI) m/z: 293.1 (M+H⁺).

Example A11

A suspension of Pd(PPh₃)₄ (0.092 g, 0.079 mmol), K₂CO₃ (0.659 g, 4.77mmol), 2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)thiazole(0.429 g, 1.908 mmol) and Example A1 (0.4 g, 1.590 mmol) in dioxane (6mL) and water (1.5 mL) was sparged with Ar and heated at 90° C.overnight. The mixture was cooled to RT, treated with brine, extractedwith EtOAc (3×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to afford2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (191 mg,38%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.61 (d, J=2.8 Hz, 1H), 8.52 (d,J=5.7 Hz, 1H), 8.42 (d, J=8.9 Hz, 1H), 8.35 (s, 1H), 8.02 (dd, J=8.9,2.8 Hz, 1H), 7.79 (d, J=2.4 Hz, 1H), 7.10 (dd, J=5.7, 2.4 Hz, 1H), 2.65(s, 3H); MS(ESI) m/z: 315.1 (M+H⁺).

A 0° C. solution of2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole (0.191 g,0.608 mmol) in THF (3 mL) and MeOH (3 mL) was treated with NH₄Cl (1.3 g,24.31 mmol) followed by the slow addition of zinc dust (0.397 g, 6.08mmol), the mixture allowed to warm to RT and stirred for 2 h. Themixture was treated with THF, the solids removed via filtration throughdiatomaceous earth, washed well with THF, the filtrate treated withEtOAc, washed with 1:1 brine/satd. NaHCO₃, dried over Na₂SO₄ andconcentrated to dryness to afford5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (164 mg,95%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (d, J=5.8 Hz, 1H), 8.28 (s, 1H),7.82 (d, J=2.9 Hz, 1H), 7.50 (d, J=2.4 Hz, 1H), 7.29 (dd, J=8.9, 3.0 Hz,1H), 6.67 (dd, J=5.8, 2.4 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.03 (s, 2H),2.64 (s, 3H); MS(ESI) m/z: 285.1 (M+H⁺).

Example A12

A mixture of Example C7 (1.185 g, 3.93 mmol), Example A6 (0.746 g, 2.81mmol), K₂CO₃ (1.165 g, 8.43 mmol) and Pd(PPh₃)₄ (0.325 g, 0.281 mmol) indioxane (11 mL) and water (3 mL) was sparged with Ar and heated at 90°C. overnight. The mixture was cooled to RT, treated with EtOAc and brineand the solids removed via filtration through diatomaceous earth. Thelayers of the filtrate were separated, the aqueous layer extracted withadditional EtOAc (3×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to afford2-methyl-3-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)-6-nitropyridine(553 mg, 49%). MS (ESI) m/z: 405.2 (M+H⁺).

A solution of2-methyl-3-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)-6-nitropyridine(0.553 g, 1.367 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% w/wwater, 146 mg, 0.137 mmol) and hydrogenated (1 atm) overnight. Thesolids were removed via filtration, washed with MeOH and the filtrateconcentrated to dryness to afford6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine(446 mg, 87%). MS (ESI) m/z: 375.2 (M+H⁺).

Example A13

A suspension of Example A8 (1.3 g, 4.65 mmol) and NH₄Cl (7.5 g, 140mmol) in MeOH (24 mL) and THF (24 mL) was treated portion-wise with zincdust (3 g, 45.9 mmol) and stirred at RT overnight. The solids wereremoved via filtration through diatomaceous earth and the filtrateconcentrated to dryness to afford5-((2-chloropyridin-4-yl)oxy)-6-ethylpyridin-2-amine (1.1 g, 85%). MS(ESI) m/z: 250.1 (M+H⁺).

Example A14

A mixture of Example C6 (2 g, 5.15 mmol), Example A6 (1.053 g, 3.96mmol) and Pd(PPh₃)₄ (0.229 g, 0.198 mmol) in toluene (20 mL), spargedwith Ar and heated at 105° C. overnight. The mixture was cooled to RT,treated 10% KF (aq) and EtOAc and stirred at RT for 2 h. The solids wereremoved via filtration through diatomaceous earth, washed with EtOAc andthe filtrate was washed with satd. NaHCO₃, then brine, dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to afford2-methyl-5-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2 azole (1.06g, 81%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.50 (d, J=5.7 Hz, 1H), 8.34 (s,1H), 8.24 (d, J=8.7 Hz, 1H), 7.88 (d, J=8.7 Hz, 1H), 7.72 (d, J=2.4 Hz,1H), 7.02 (dd, J=5.7, 2.4 Hz, 1H), 2.65 (s, 3H), 2.50 (s, 3H); MS (ESI)m/z: 329.1 (M+H⁺).

A solution of2-methyl-5-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)thiazole(1.06 g, 3.23 mmol) in MeOH (40 mL) was treated with 10% Pd/C (50% w/wwater, 0.344 g, 0.323 mmol) and hydrogenated (50 psi) overnight.Additional 10% Pd/C (50% w/w water, 0.344 g, 0.323 mmol) was added andthe mixture hydrogenated (50 psi) for an additional 24 h. The solidswere removed via filtration through diatomaceous earth, washed with MeOHand the filtrate concentrated to dryness. The material was treated withMTBE, the solid collected via filtration and dried to afford6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine(860 mg, 89%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.34 (d, J=5.8 Hz, 1H), 8.28(s, 1H), 7.49 (d, J=2.4 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 6.58 (dd,J=5.8, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.96 (s, 2H), 2.65 (s, 3H),2.07 (s, 3H); MS (ESI) m/z: 299.1 (M+H⁺).

Example A15

A mixture of 2,4-dimethyl-3-hydroxypyridine (3.00 g, 24.36 mmol) andNa₂CO₃ (5.16 g, 48.7 mmol) in MeOH (40 mL) and water (24 mL) was treatedwith iodine (6.18 g, 24.36 mmol) and stirred at RT for 1 h. Additionaliodine (0.4 g) was added, the mixture stirred at RT for 3 h, thenacidified to pH=5 with 3M HCl. The mixture was treated with brine,extracted with EtOAc (2×) and the combined organics were washed withbrine, dried over Na₂SO₄ and concentrated to dryness to afford6-iodo-2,4-dimethylpyridin-3-ol (5.1 g, 84%). MS (ESI) m/z: 250.0(M+H⁺).

A solution of 6-iodo-2,4-dimethylpyridin-3-ol (5.10 g, 20.48 mmol) inDMA (60 mL) was sparged with Ar, treated with 2,4-dichloropyridine (3.94g, 26.60 mmol) and K₂CO₃ (3.40 g, 24.57 mmol) and heated at 105° C.overnight. The mixture was cooled to RT, treated with EtOAc and water,filtered to remove solids, then treated with charcoal, warmed to reflux,cooled to RT and filtered through diatomaceous earth. The layers of thefiltrate were separated, the aqueous layer extracted with additionalEtOAc (1×) and the combined organics were washed with brine, dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to afford3-((2-chloropyridin-4-yl)oxy)-6-iodo-2,4-dimethylpyridine (1.476 g,20%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, J=5.8 Hz, 1H), 7.75 (s, 1H),7.05 (d, J=2.3 Hz, 1H), 6.89 (dd, J=5.8, 2.3 Hz, 1H), 2.20 (s, 3H), 2.02(s, 3H); MS (ESI) m/z: 361.0 (M+H⁺).

A mixture of 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2,4-dimethylpyridine(1.45 g, 4.02 mmol), acetamide (950 mg, 16.09 mmol), Cs₂CO₃ (1.965 g,6.03 mmol) and X-phos (96 mg, 0.201 mmol) in dioxane (25 mL) was spargedwith Ar, treated with Pd₂(dba)₃ (184 mg, 0.201 mmol), sparged again withAr and heated at 85° C. overnight. The mixture was cooled to RT, dilutedwith EtOAc and the solids removed via filtration through diatomaceousearth. The filtrate was washed with water, then brine, dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to affordN-(5-((2-chloropyridin-4-yl)oxy)-4,6-dimethylpyridin-2-yl)acetamide (598mg, 51%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.53 (s, 1H), 8.26 (d, J=5.8 Hz,1H), 7.94 (s, 1H), 6.99 (d, J=2.3 Hz, 1H), 6.85 (dd, J=5.8, 2.3 Hz, 1H),2.17 (s, 3H), 2.06 (d, J=1.7 Hz, 6H); MS (ESI) m/z: 292.1 (M+H⁺).

A mixture ofN-(5-((2-chloropyridin-4-yl)oxy)-4,6-dimethylpyridin-2-yl)acetamide (598mg, 2.05 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(554 mg, 2.66 mmol), K₂CO₃ (850 mg, 6.15 mmol) and Pd(PPh₃)₄ (118 mg,0.102 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar andheated at 80° C. overnight. The mixture was cooled to RT, diluted withEtOAc, washed with satd. NaHCO₃, then brine, dried over Na₂SO₄ andconcentrated to dryness to afford crudeN-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide(100% yield assumed) which was used without further purification. MS(ESI) m/z: 338.1 (M+H⁺).

A solution ofN-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide(692 mg, 2.051 mmol) in THF (25 mL) was treated with HCl (3 M, 3.4 mL,10.2 mmol) and warmed at 40° C. for 17 h. The mixture was treated withsatd. NaHCO₃, extracted with EtOAc (2×) and the combined organics weredried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/EtOAc) to afford4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(446 mg, 73%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.30 (d, J=5.7 Hz, 1H), 8.23(s, 1H), 7.93 (d, J=0.7 Hz, 1H), 7.10 (d, J=2.4 Hz, 1H), 6.44 (dd,J=5.7, 2.4 Hz, 1H), 6.22 (s, 1H), 5.81 (s, 2H), 3.84 (s, 3H), 2.02 (s,3H), 1.92 (s, 3H); MS (ESI) m/z: 296.1 (M+H⁺).

Example A16

A mixture of toluene (60 mL) and dioxane (12 mL) was sparged with Ar,treated with Pd₂(dba)₃ (0.255 g, 0.278 mmol) and Me₄tBuXPhos[di-tert-butyl(2′,4′,6′-triisopropyl-3,4,5,6-tetramethyl-[1,1′-biphenyl]-2-yl)phosphine](0.267 g, 0.556 mmol) and heated at 120° C. for 15 min, partiallycooled, treated with Example A1 (3.5 g, 13.91 mmol), K₃PO₄ (5.91 g, 27.8mmol) and 4-methylimidazole (3.43 g, 41.7 mmol) and heated at 120° C.overnight. The mixture was cooled to RT, treated with brine andextracted with EtOAc (2×). The combined organics were washed with brine(2×), dried over MgSO₄, concentrated to dryness and purified via silicagel chromatography (EtOAc/Hex) to afford2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.3g, 31%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.64-8.63 (m, 1H), 8.44-8.43 (m,2H), 8.41 (d, J=1.4 Hz, 1H), 8.06 (dd, J=8.9, 2.8 Hz, 1H), 7.65 (t,J=1.3 Hz, 1H), 7.56 (d, J=2.2 Hz, 1H), 7.12 (dd, J=5.7, 2.2 Hz, 1H),2.13 (d, J=1.0 Hz, 3H); MS (ESI) m/z: 298.1 (M+H⁺).

A solution of2-(4-methyl-1H-imidazol-1-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.3g, 4.37 mmol) in MeOH (20 mL)/THF (20 mL) was treated sequentially withNH₄Cl (7.02 g, 131 mmol) and zinc dust (2.86 g, 43.7 mmol) and stirredat RT for 2 h. The mixture was diluted with THF, the solids removed viafiltration through diatomaceous earth, washed with THF and the filtrateconcentrated to dryness. The material was treated with THF, the solidsremoved via filtration and the filtrate concentrated to dryness, treatedwith DCM and sonicated. The resulting solid was collected via filtrationand dried to afford5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-amine (800mg, 68%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.39 (d, J=1.4 Hz, 1H), 8.28 (d,J=5.8 Hz, 1H), 7.83 (d, J=2.9 Hz, 1H), 7.63 (s, 1H), 7.31-7.30 (m, 2H),6.70 (dd, J=5.8, 2.2 Hz, 1H), 6.51 (d, J=8.9 Hz, 1H), 6.05 (s, 2H), 2.14(d, J=1.0 Hz, 3H); MS (ESI) m/z: 268.2 (M+H⁺).

Example A17

A mixture of Example A1 (1.5 g, 5.96 mmol),N-methyl-4-(tributylstannyl)imidazole (3.32 g, 8.94 mmol) and Pd(PPh₃)₄(0.344 g, 0.298 mmol) in toluene (30 mL) sparged with Ar and heated at110° C. overnight. The mixture was cooled to RT, treated with 10% KF andEtOAc, stirred at RT for 2 h, the solids removed via filtration throughdiatomaceous earth and washed with 5% MeOH/DCM. The layers of thefiltrate were separated and the organic layer was washed with brine,dried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM). The material was washed with a small amountof Et₂O and dried to afford2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61g, 91%). MS (ESI) m/z: 298.1 (M+H⁺).

A solution of2-(1-methyl-1H-imidazol-4-yl)-4-((6-nitropyridin-3-yl)oxy)pyridine (1.61g, 5.42 mmol) in MeOH (30 mL) was treated with 10% Pd/C (50% w/w water,0.576 g, 0.542 mmol) and hydrogenated (50 psi) overnight. The solidswere removed via filtration through diatomaceous earth, washed with warmMeOH and the filtrate was concentrated to dryness to afford5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine (1.311g, 91%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (d, J=5.7 Hz, 1H), 7.81 (d,J=2.9 Hz, 1H), 7.65 (d, J=1.3 Hz, 1H), 7.58 (s, 1H), 7.29 (dd, J=8.9,3.0 Hz, 1H), 7.19 (d, J=2.6 Hz, 1H), 6.73 (dd, J=5.7, 2.6 Hz, 1H), 6.52(d, J=8.9 Hz. 1H), 6.03 (s, 2H), 3.67 (s, 3H); MS (ESI) m/z: 268.1(M+H⁺).

Example A18

A 0° C. solution of H₂SO₄ (12 mL) was treated with H₂O₂ (9.72 mL, 95mmol), stirred for 10 min, treated with a solution of2-amino-5-fluoro-4-methylpyridine (2 g, 15.86 mmol) in H₂SO₄ (8 mL),stirred for 15 min, then warmed to RT and stirred for 3 h. The mixturewas re-cooled to 0° C., neutralized slowly with solid NaHCO₃ and theresulting solid collected via filtration and dried to afford5-fluoro-4-methyl-2-nitropyridine (2 g, 81%). ¹H NMR (400 MHz, DMSO-d₆):δ 8.57 (s, 1H), 8.42 (d, J=5.3 Hz, 1H), 2.42 (d, J=1.9 Hz, 3H); MS (ESI)m/z: 157.1 (M+H⁺).

A mixture of 5-fluoro-4-methyl-2-nitropyridine (2 g, 12.81 mmol) and2-chloro-4-hydroxypyridine (1.66 g, 12.81 mmol) in DMF (26 mL) wassparged with Ar, treated with K₂CO₃ (2.66 g, 19.22 mmol), heated at 88°C. for 24 h, then at 50° C. for 2 days. The mixture was treated withwater and the resulting solid collected via filtration and dried toafford 5-((2-chloropyridin-4-yl)oxy)-4-methyl-2-nitropyridine (2.72 g,80%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.49 (s, 1H), 8.47 (s, 1H), 8.35 (d,J=5.7 Hz, 1H), 7.24 (d, J=2.3 Hz, 1H), 7.12 (dd, J=5.7, 2.3 Hz, 1H),2.32 (s, 3H); MS (ESI) m/z: 266.0 (M+H⁺).

Example A19

A mixture of Example A18 (0.48 g, 1.807 mmol) and NH₄Cl (2.90 g, 54.2mmol) in MeOH (4.5 mL) and THF (4.5 mL) was treated portion-wise withzinc dust (1.182 g, 18.07 mmol) and stirred at RT for 1 h. The mixturewas diluted with EtOAc, the solids removed via filtration throughdiatomaceous earth and the filtrate concentrated to dryness to afford5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-amine (400 mg, 94%). MS(ESI) m/z: 236.1 (M+H⁺).

Example A20

Anhydrous DMF (150 mL) was added to 60% NaH in mineral oil (2.72 g, 67.9mmol) under an Ar atmosphere, cooled in an ice bath, treatedportion-wise with a solution of 2-chloropyridin-4-ol (8 g, 61.8 mmol) inDMF (30 mL) and stirred cold for 5 minutes. The cooling bath was removedand the mixture was warmed to RT and stirred for 20 minutes.1,2,4-Trifluoro-5-nitrobenzene (13.12 g, 74.1 mmol) was added and thereaction mixture heated at 90° C. for 3 h. The reaction mixture wascooled to RT, concentrated to dryness, treated with EtOH (50 mL) andMeOH (20 mL), warmed gently, then cooled to RT. The yellow solid wascollected by filtration, rinsed with EtOH (50 mL) and hexanes (20 mL)and dried under vacuum overnight to provide2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine as a yellow solid(11.68 g, 63% yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (dd, J=10.2, 7.0Hz, 1H), 8.41 (d, J=5.6 Hz, 1H), 7.90 (dd, J=11.6, 6.7 Hz, 1H), 7.41 (d,J=2.1 Hz, 1H), 7.26 (dd, J=5.6, 2.4 Hz, 1H); MS (ESI): m/z 287.0 [M+H]⁺

A solution of 2-chloro-4-(2,5-difluoro-4-nitrophenoxy)pyridine (11.68 g,40.8 mmol) in MeOH (200 mL) was treated with Raney Ni (50% wet, 0.955 g,8.15 mmol) and hydrogenated (10-20 psi) for 4 h. The mixture wasfiltered through a pad of diatomaceous earth and the filtrate wasconcentrated to dryness to provide4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (8.2 g, 72% yield). ¹HNMR (400 MHz, DMSO-d₆): δ 8.28 (d, J=5.9 Hz, 1H), 7.25 (dd, J=11.2, 7.5Hz, 1H), 7.02 (dd, J=2.2 Hz, 1H), 6.95 (dd, J=5.8, 2.0 Hz, 1H), 6.74(dd, J=12.3, 8.3 Hz, 1H), 5.57 (s, 2H); MS (ESI): m/z 257.0 [M+H]⁺

A solution of 4-(2-chloropyridin-4-yloxy)-2,5-difluoroaniline (450 mg,1.76 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(400 mg, 1.9 mmol) in DMF (30 mL) was treated withtetrakis(triphenylphosphine)palladium(0) [Pd(PPh₃)₄] (105 mg, 0.09 mmol)and an aqueous solution of potassium phosphate (2 M, 1.8 mL). Themixture was flushed with nitrogen for 10 min, and then heated at 90° C.overnight. After cooling to RT, the mixture was treated with water,extracted with EtOAc (4×) and the combined organics were washed withbrine, dried (Na₂SO₄), concentrated under reduced pressure and purifiedby silica gel chromatography to give2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline(335 mg, 63% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.35 (d, J=5.7 Hz,1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.24-7.18 (m, 2H), 6.75 (dd, J=1 2.3,8.1 Hz, 1H), 6.62 (dd, J=5.4, 2.1 Hz, 1H), 5.53 (br s, 2H), 3.87 (s,3H); MS (ESI): m/z 303.1 [M+1]⁺.

Example A21

A 0° C. suspension of NaH (60% in mineral oil, 0.620 g, 15.5 mmol) inDMF (30 mL) was treated portion-wise with of 2-chloro-4-hydroxypyridine(1.339 g, 10.33 mmol), stirred at 0° C. for 0.5 h, slowly warmed to RT,treated with a solution of 5-chloro-2,4-difluoronitrobenzene (2 g, 10.33mmol) in DMF (4.4 mL) and heated at 90° C. for 15 h. The mixture wascooled to RT, diluted with EtOAc, washed with 10% LiCl (3×), then brine(2×), dried over MgSO₄, concentrated to dryness and purified via silicagel chromatography (EtOAc/Hex) to afford2-chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine (1.415 g, 45%). ¹HNMR (400 MHz, DMSO-d₆): δ 8.56 (dd, 1H), 8.35 (dd, 1H), 7.88 (dd, 1H),7.32 (dd, 1H), 7.18 (m, 1H); MS (ESI) m/z: 303.0 (M+H⁺).

A mixture of 2-chloro-4-(2-chloro-5-fluoro-4-nitrophenoxy)pyridine(1.306 g, 4.31 mmol) and NH₄Cl (2.305 g, 43.1 mmol) in THF (108 mL) andMeOH (108 mL) was treated with zinc dust (2.82 g, 43.1 mmol) and stirredat RT for 1 h. The solids were removed via filtration throughdiatomaceous earth and the filtrate concentrated under reduced pressureto afford 5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline (100%yield assumed) as a brown solid which was used without purification. MS(ESI) m/z: 273.0 (M+H⁺).

Example A22

A solution of Example A21 (1.177 g, 4.31 mmol) and1-methyl(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.166g, 5.60 mmol) in DMF (16 mL) was treated with Cs₂CO₃ (4.21 g, 12.93mmol) and water (5 mL), sparged with Ar, treated with Pd(PPh₃)₄ (0.249g, 0.215 mmol) and heated at 90° C. for 4 h. The mixture was cooled toRT, diluted with 4:1 EtOAc/THF, washed with 10% LiCl (2×), then brine(1×), dried over MgSO₄, evaporated under reduced pressure and purifiedvia silica gel chromatography (EtOAc/Hex) to yield5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)anilineas a tan solid (1.062 g, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.31 (d,1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.20 (d, 1H), 7.13 (d, 1H), 6.92 (d,1H), 6.52 (dd, 1H), 5.49 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 319.1(M+H⁺).

Example A23

DMF (25 mL) was slowly treated with SOCl₂ (125 mL) to maintain atemperature of 40-50° C. The mixture was then treated portion-wise withpyridine-2-carboxylic acid (25 g, 0.2 mol) over 0.5 h, then heated atreflux for 16 h, cooled to RT, diluted with toluene (80 mL) andconcentrated to dryness (this process was repeated three times). Theresulting residue was washed with toluene and dried under reducedpressure to yield 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 79%yield), which was used in the next step without purification.

A 0° C. solution of 4-chloro-pyridine-2-carbonyl chloride (27.6 g, 0.16mol) in THF (100 mL) at was treated drop-wise with a solution of MeNH₂in EtOH, stirred at 3° C. for 4 h, then concentrated to dryness. Thematerial was suspended in EtOAc, the solids removed via filtration andthe filtrate was washed with brine (2×), dried and concentrated to yield4-chloro-N-methylpicolinamide (16.4 g, 60%) as a yellow solid. ¹H NMR(400 MHz, DMSO-d₆) δ 8.78 (br s, 1H), 8.55 (d, J=5.2 Hz, 1H), 7.97 (d,J=2.0 Hz, 1H), 7.66 (m, 1H), 2.82 (d, J=4.8 Hz, 3H); MS (ESI) m/z: 171.0(M+H⁺).

A solution of 2-amino5-hydroxypyridine (0.968 g, 8.79 mmol) in DMA (15mL) was treated with potassium tert-butoxide (0.987 g, 8.79 mmol),stirred at RT for 3 h, treated with 4-chloro-N-methylpicolinamide (1.5g, 8.79 mmol) and stirred at RT for 2 days. The mixture was concentratedto dryness, treated with water, extracted with EtOAc (3×) and thecombined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc, MeOH/DCM) to afford4-((6-aminopyridin-3-yl)oxy)-N-methylpicolinamide (1.3 g, 61%). ¹H NMR(400 MHz, DMSO-d₆): δ 8.75 (m, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.82 (d,J=2.9 Hz, 1H), 7.34 (d, J=2.6 Hz, 1H), 7.30 (dd, J=8.9, 3.0 Hz, 1H),7.10 (dd, J=5.6, 2.7 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H), 6.07 (s, 2H), 2.77(d, J=4.8 Hz, 3H); MS (ESI) m/z: 245.1 (M+H⁺).

Example A24

A mixture of Example A1 (1 g, 3.97 mmol) in dioxane (20 mL) was spargedwith Ar, treated with N,N-dimethyl urea (0.700 g, 7.95 mmol) and Cs₂CO₃(1.942 g, 5.96 mmol), sparged with Ar, treated with dppf[1,1′-bis(diphenylphosphino)ferrocene] (12.38 g, 22.33 mmol) andPd₂(dba)₃ (0.182 g, 0.199 mmol), sparged once again with Ar and heatedat 95° C. overnight. The mixture was cooled to RT, treated with EtOAcand the solids removed via filtration through silica gel. The filtratewas concentrated to dryness and purified twice via silica gelchromatography (MeOH/DCM) to afford1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (616 mg,51%). MS(ESI) m/z: 304.1 (M+H⁺).

A solution of1,1-dimethyl-3-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)urea (0.631 g,2.081 mmol) in MeOH (20 mL) was treated with NH₄Cl (3.34 g, 62.4 mmol)followed by zinc dust (1.361 g, 20.81 mmol) and stirred at RT overnight.The solids were removed via filtration, washed with THF and the filtrateconcentrated to dryness to afford3-(4-((6-aminopyridin-3-yl)oxy)pyridin-2-yl)-1,1-dimethylurea (560 mg,98%). MS(ESI) m/z: 274.1 (M+H⁺).

Example A25

A mixture of Example A1 (600 mg, 2.38 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (648 mg,3.10 mmol), K₂CO₃ (989 mg, 7.15 mmol) and Pd(PPh₃)₄ (138 mg, 0.119 mmol)in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80°C. overnight. Additional2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)oxazole (100 mg)and Pd(PPh₃)₄ (50 mg) were added, the mixture heated at 80° C. for 5 h,then cooled to RT and treated with water and EtOAc. The solids wereremoved via filtration through diatomaceous earth, the layers of thefiltrate separated and the organic layer was washed with brine, driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/EtOAc) to afford2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (323 mg,45%). MS (ESI) m/z: 299.1 (M+H⁺).

A 0° C. mixture of2-methyl-5-(4-((6-nitropyridin-3-yl)oxy)pyridin-2-yl)oxazole (323 mg,1.083 mmol) and NH₄Cl (2.317 g, 43.3 mmol) in MeOH (8 mL) and THF (8 mL)was treated portion-wise with zinc dust (708 mg, 10.83 mmol), allowed towarm to RT and stirred overnight. The mixture was diluted with EtOAc,warmed slightly, the solids removed via filtration through diatomaceousearth and washed with EtOAc. The filtrate was concentrated to dryness,treated with EtOAc, heated to reflux, the solids removed via hotfiltration and the filtrate concentrated to dryness to afford5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (324 mg,112%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.43 (d, J=5.7 Hz, 1H), 7.83 (d,J=2.9 Hz, 1H), 7.60 (s, 1H), 7.31 (dd, J=8.9, 3.0 Hz, 1 H), 7.06 (d,J=2.5 Hz, 1H), 6.83 (dd, J=5.7, 2.5 Hz, 1H), 6.53 (d, J=8.9 Hz, 1H),6.07 (s, 2H), 2.46 (s, 3H); MS (ESI) m/z: 269.1 (M+H⁺).

Example A26

A mixture of Example A7 (905 mg, 3.84 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.010g, 4.61 mmol), potassium carbonate (1.592 g, 11.52 mmol) andtetrakis(triphenylphosphine)palladium(0) (222 mg, 0.192 mmol) in dioxane(16 mL) and water (4 mL) was degassed with Ar, sealed and warmed to 85°C. overnight. The mixture was cooled to RT, diluted with EtOAc (40 mL)and water (50 mL), and filtered through diatomaceous earth. The organicphase was separated and washed with brine (50 mL). The organic phase wasdiluted with methanol (5 mL), treated with SiliaMetS Thiol, (1.42mmol/g, 4 g, 5.68 mmol), and gently stirred for 3 h. The mixture wasfiltered, washing the silica gel plug with 3% MeOH/EtOAc (2×10 mL). Thefiltrates were evaporated at reduced pressure and the residue waspurified by silica gel chromatography (0-10% MeOH/EtOAc) to give6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine as atan solid (806 mg, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (d, J=2.3 Hz,1H), 8.48 (d, J=5.7 Hz, 1H), 8.25 (dd, J=8.1, 2.4 Hz, 1H), 7.50 (d,J=2.4 Hz, 1H), 7.33 (d, J=8.2 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.67 (dd,J=5.7, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.96 (s, 2H), 2.50 (s, 3H),2.08 (s, 3H). MS (ESI) m/z: 293.2 (M+H⁺).

Example A27

A solution of 2-amino-5-hydroxypyrimidine (1.00 g, 9.00 mmol) in DMA (25mL) was treated with potassium tert-butoxide (1.24 g, 11.05 mmol). Thethick mixture was stirred at room temperature for 1 h. To this was addeda solution of 2,4-dichloropyridine (1.21 g, 8.18 mmol) in DMA (10 mL)and the reaction was stirred at RT overnight under Ar. The mixture wasdiluted with EtOAc (100 mL) and washed with water (100 mL). The organicphase was separated and the aqueous was extracted with EtOAc (100 mL).The combined EtOAc layers were washed with 5% LiCl (100 mL) and brine(100 mL) and then dried over sodium sulfate. The solvents wereevaporated at reduced pressure to give5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine as a pale yellow solid(592 mg, 32%). MS (ESI) m/z: 223.0 (M+H⁺).

5-((2-chloropyridin-4-yl)oxy)pyrimidin-2-amine (676 mg, 3.04 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(758 mg, 3.64 mmol), potassium carbonate (1.259 g, 9.11 mmol) andtetrakis(triphenylphosphine)palladium(0) (175 mg, 0.152 mmol) werecombined in dioxane (12 mL) and water (3 mL). The mixture was degassedwith argon, sealed and warmed to 85° C. overnight. The mixture wasdiluted with EtOAc (75 mL) and water (40 mL) and was filtered to collectan off-white solid. The organic phase was separated, washed with brine(40 mL) and evaporated at reduced pressure to give additional off-whitesolid. The two crops of solids were combined and triturated with EtOAc(15 mL) with sonication. The solid was collected by filtration, washedwith EtOAc (2×5 mL) and dried under vacuum to provide5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-amine (455mg, 55%). ¹H NMR (DMSO-d₆): δ 8.34 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 8.22(s, 2H), 7.96 (s, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.77 (s, 2H), 6.67 (dd,J=5.7, 2.5 Hz, 1H,), 3.84 (s, 3H); MS (ESI) m/z: 269.1 (M+H⁺).

Example A28

A solution of Example A6 (1.7 g, 6.40 mmol) in dioxane (30 mL) wassparged with Ar, treated with acetamide (1.512 g, 25.6 mmol), Cs₂CO₃(2.085 g, 6.40 mmol), X-Phos (0.153 g, 0.320 mmol) and Pd₂(dba)₃ (0.293g, 0.320 mmol) and heated at 80° C. for 20 h. The mixture was cooled toRT, treated with EtOAc, the solids removed via filtration throughdiatomaceous earth and rinsed well with EtOAc. The filtrate was washedwith water, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (EtOAc/DCM) to affordN-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (450 mg,24%) as a light yellow solid. MS(ESI) m/z: 289.1 (M+H⁺).

A solution ofN-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)acetamide (0.44 g,1.526 mmol) in MeOH (30 mL) was treated with palladium on carbon (50%wet, 0.162 g, 0.153 mmol) and hydrogenated (1 atm) at RT for 24 h. Thesolids were removed via filtration through diatomaceous earth, washedwell with MeOH and the filtrate concentrated to affordN-(4-((6-amino-2-methylpyridin-3-yl)oxy)pyridin-2-yl)acetamide (370 mg,94%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.46 (s, 1H), 8.10(d, J=5.7 Hz, 1H), 7.53 (d, J=2.3 Hz, 1H), 7.13 (d, J=8.7 Hz, 1H), 6.53(dd, J=5.7, 2.4 Hz, 1H), 6.32 (d, J=8.7 Hz, 1H), 5.91 (s, 2H), 2.02 (s,3H), 2.01 (s, 3H); MS(ESI) m/z: 259.2 (M+H⁺).

Example B1

A RB flask was charged with 4-aminotetrahydropyran (9.77 g, 97 mmol) inTHF (480 mL) and was cooled in an ice bath. To this stirring solutionwas added 2-chloroethyl isocyanate (11.19 g, 106 mmol) drop-wise and thereaction was brought to RT and stirred at RT overnight. The reactionmixture was concentrated to dryness and the crude product was washedsuccessively with saturated NH₄Cl (60 mL) and saturated NaHCO₃ (60 mL).The organic layer was dried over anhydrous Na₂SO₄ and concentrated todryness to afford a white solid. Toluene (20 mL) was added and theresidue was concentrated to dryness. The process was repeated a secondtime (to remove any moisture) to afford1-(2-chloroethyl)-3-(tetrahydro-2H-pyran-4-yl)urea as a white solid. Theproduct was utilized in the next reaction without purification. ¹H NMR(CDCl₃): δ 5.34-4.94 (bs, 1H), 4.93-4.56 (bs, 1H), 3.94 (dt, J=11.9, 3.2Hz, 2H), 3.84-3.71 (m, 1H), 3.64-3.59 (m, 2H), 3.49-3.47 (m, 2H),1.95-1.83 (m, 2H), 1.50-1.34 (m, 2H); MS (ESI) m/z: 207.1 (M+H⁺).

A dry RB flask charged with1-(2-chloroethyl)-3-(tetrahydro-2H-pyran-4-yl)urea (19.96 g, 97 mmol) inTHF (480 mL), placed under Ar and stirred for 20 minutes at −20° C.after which 60% Sodium Hydride in mineral oil (9.66 g, 241 mmol) wasadded portion wise. The reaction was allowed to stir at −20° C. for 1 hand was then allowed to warm to ambient temp overnight. The reaction wascooled in an ice bath and quenched via slow addition of saturated NH₄Cl(50 mL). Brine (30 mL) was added and the reaction was allowed to stirfor 20 minutes. The organic layer was separated and aqueous layerextracted with EtOAc (2×) and THF (2×). The organic layers werecombined, dried over anhydrous Na₂SO₄ and concentrated to dryness toafford a white gummy solid. The crude product was purified by silica gelchromatography (5% MeOH in CH₂Cl₂) to afford1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one as a white solid (10.54g, 64% yield, 2 steps). ¹H NMR (DMSO-d₆): δ 6.24 (s, 1H), 3.91-3.81 (m,2H), 3.73-3.61 (m, 1H), 3.29-3.23 (m, 2H), 3.22-3.21 (m, 2H), 3.19-3.14(m, 2H), 1.67-1.53 (m, 2H), 1.45-1.44 (m, 2H); MS (ESI) m/z: 171.1(M+H⁺).

Example B2

A 0° C. solution of phosgene (20% in toluene, 0.267 mL, 0.506 mmol) inDCM (5 mL) was treated slowly drop-wise with a solution of Example B1(0.086 g, 0.505 mmol) and pyridine (0.082 mL, 1.011 mmol) in DCM (3 mL).The mixture was warmed to RT, stirred for 1 hour, then concentrated todryness to afford2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carbonyl chloride asan off-white solid. The material was carried on to the next stepassuming 100% yield (118 mg). MS (ESI) m/z: 304.1 (M+H⁺) (for materialquenched into benzylamine).

Example B3

A solution of methoxyethylamine (0.40 mL, 4.60 mmol) in THF (15 mL) wastreated with 2-chloroethylisocyanate (0.35 mL, 4.10 mmol), stirred at RTfor 3 h and concentrated to dryness to afford1-(2-chloroethyl)-3-(2-methoxyethyl)urea (100% yield assumed) as a whitesolid. MS (ESI) m/z: 181.1 (M+H⁺).

A −20° C. solution of 1-(2-chloroethyl)-3-(2-methoxyethyl)urea (0.300 g,1.661 mmol) in THF (8.3 mL), under Ar, was treated with NaH (60% inmineral oil, 0.166 g, 4.15 mmol) allowed to warm to RT and stirred. Themixture was cooled to 0° C., treated slowly with satd. NH₄Cl, thenbrine, warmed to RT and stirred for 20 min. The layers were separated,the aqueous layer extracted with EtOAc (2×) and the combined organicswere dried over Na₂SO₄, concentrated to dryness and purified via silicagel chromatography (MeOH/DCM) to afford1-(2-methoxyethyl)imidazolidin-2-one (220 mg, 92%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 6.26 (s, 1H), 3.39-3.31 (m, 4H), 3.22 (s, 3H),3.20-3.14 (m, 4H); MS (ESI) m/z: 145.1 (M+H⁺).

Example B4

A 0° C. solution of phosgene (20% in toluene, 0.642 mL, 6.07 mmol) inDCM (12 mL) was treated drop-wise with a solution of pyridine (0.196 mL,2.428 mmol) and Example B3 (0.175 g, 1.214 mmol) in DCM (10 mL) allowedto warm to RT and stirred for 1 h. The mixture was concentrated todryness to afford crude 3-(2-methoxyethyl)-2-oxoimidazolidine-1-carbonylchloride (100% yield assumed) which was used without furtherpurification. 3-(2-Methoxyethyl)-2-oxoimidazolidine-1-carbonyl chloridewas characterized as a benzylamine addition product (C₁₄H₁₉N₃O₃). MS(quenched into benzyl amine) (ESI) m/z: 278.2 (C₁₄H₁₉N₃O₃+H⁺).

Example B5

A solution of 3-methoxypropylamine (0.45 mL, 4.39 mmol) in THF (15 mL)was treated with 2-chloroethylisocyanate (0.35 mL, 4.10 mmol), stirredat RT for 3 h and concentrated to dryness to afford1-(2-chloroethyl)-3-(3-methoxypropyl)urea (100% yield assumed) as awhite solid. MS (ESI) m/z: 195.1 (M+H⁺).

A 0° C. solution of 1-(2-chloroethyl)-3-(3-methoxypropyl)urea (0.300 g,1.541 mmol) in THF (8 mL), under Ar, was treated with NaH (60% inmineral oil, 0.154 g, 3.85 mmol) allowed to warm to RT and stirred. Themixture was cooled to 0° C., treated slowly with satd. NH₄Cl, thenbrine, warmed to RT and stirred for 10 min. The layers were separated,the aqueous layer extracted with EtOAc (2×) and the combined organicswere dried over Na₂SO₄, concentrated to dryness and purified via silicagel chromatography (MeOH/DCM) to afford1-(3-methoxypropyl)imidazolidin-2-one (214 mg, 88%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 6.21 (s, 1H), 3.31-3.24 (m, 4H), 3.21-3.15 (m,5H), 3.06-3.01 (m, 2H), 1.66-1.58 (m, 2H); MS (ESI) m/z: 159.1 (M+H⁺).

Example B6

A solution of (S)-(−)-tetrahydro-3-furylamine p-toluenesulfonate salt(0.5 g, 1.928 mmol) in THF (20 mL) was gently agitated with MP-CarbonateResin (1.825 g, 5.78 mmol, 3.17 mmol/g loading) for 36 h, the resinremoved via filtration and the filtrate cooled to 0° C., treateddrop-wise with chloroethyl isocyanate (0.224 g, 2.121 mmol), warmed toRT and stirred overnight. The mixture was washed with satd. NH₄Cl (1×),satd. NaHCO₃ (1×), then brine (1×), dried over MgSO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford(S)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (0.11 g, 30%). ¹H NMR(400 MHz, DMSO-d₆): δ 6.31 (d, J=6.9 Hz, 1H), 6.01 (t, J=5.9 Hz, 1H),4.11-4.08 (m, 1H), 3.69-3.67 (m, 3H), 3.55 (t, J=6.2 Hz, 2H), 3.36 (dd,J=8.8, 3.8 Hz, 1H), 3.32-3.26 (m, 2H), 2.03 (dq, J=12.6, 7.6 Hz, 1H),1.59-1.61 (m, 1H); MS (ESI) m/z: 193.1 (M+H⁺).

A −20° C. solution of (S)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea(0.11 g, 0.571 mmol) in THF (6 mL) was treated with NaH (60% in mineraloil, 0.057 g, 1.428 mmol), stirred at −20° C. for 0.5 h, then at RT for1 h. The mixture was treated with satd. NH₄Cl and H₂O, extracted withEtOAc (3×) and THF (2×) and the combined organics were washed with brine(1×), dried over MgSO₄, concentrated to dryness and purified via silicagel chromatography (MeOH/DCM) to afford(S)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (26 mg, 29%). ¹H NMR (400MHz, DMSO-d₆): δ 6.32 (brs, 1H), 4.36-4.30 (m, 1H), 3.83-3.77 (m, 1H),3.63-3.53 (m, 4H), 3.31-3.26 (m, 1H), 3.24-3.21 (m, 2H); 2.05-1.96 (m,1H); 1.84-1.76 (m, 1H). MS (ESI) m/z: 157.1 (M+H⁺).

Example B7

A solution of cyclohexylamine (1.00 g, 10.08 mmol) and 2-chloroethylisocyanate (1.064 g, 10.08 mmol) in THF (30 mL) was stirred at RTfor 4 h, treated with sodium hydride (60% in mineral oil, 0.403 g, 10.08mmol) and stirred at RT for 16 h. The mixture was poured into satd.NH₄Cl, treated with solid NaCl until saturated, extracted with THF (2×)and the combined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness. The material was suspended in 30% EtOAc/Hex,stirred and the resulting solid collected via filtration to afford1-cyclohexylimidazolidin-2-one (650 mg, 38%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 6.14 (s, 1H), 3.46-3.37 (m, 1H), 3.27-3.21 (m,2H), 3.19-3.13 (m, 2H), 1.75-1.68 (m, 2H), 1.60-1.50 (m, 3H), 1.37-1.18(m, 4H), 1.09-0.98 (m, 1H).

Example B8

A solution of (S)-1-methoxypropan-2-amine (500 mg, 5.61 mmol) in THF (15mL) was treated with 2-chloroethylisocyanate (592 mg, 5.61 mmol),stirred at RT overnight, then concentrated to dryness. The residue wastreated with toluene and concentrated to dryness (twice) to afford(S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (100% yield assumed)as a white solid which was used without further purification. MS (ESI)m/z: 195.1 (M+H⁺).

A −20° C. solution of (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea(1.092 g, 5.61 mmol) in THF (25 mL) was treated portion-wise with NaH(60% in mineral oil, 505 mg, 12.62 mmol), allowed to warm to RT andstirred overnight. The mixture was treated with EtOAc, water, then 5%citric acid, the layers separated and the organic layer washed withbrine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/EtOAc) to afford(S)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (95 mg, 11%). MS (ESI)m/z: 159.1 (M+H⁺).

Example B9

A solution of ethyl 3-aminopropanoate hydrochloride (80.0 g, 0.52 mol),benzylbromide (186.7 g, 1.1 mol) and K₂CO₃ (179.4 g, 1.3 mol) in MeCN (1L) was heated at 40° C. overnight. The mixture was concentrated todryness, poured into water, extracted with EtOAc (3×) and the combinedorganics were washed with brine, dried over Na₂SO₄ and purified viasilica gel chromatography to give ethyl 3-(dibenzylamino)propanoate (150g, 97%).

Titanium isopropoxide (860 mg, 3.03 mmol) was added to a solution ofethyl 3-(dibenzylamino)propanoate (9.0 g, 30.3 mmol) in Et2O, cooled to0° C., treated drop-wise with ethyl magnesium bromide (3M in Et₂O, 30.3mL) over 1 h, maintaining the temperature at 0˜4° C., then allowed towarm to RT and stirred overnight. The mixture was cooled to 0° C.,treated with satd. NH₄Cl, stirred at RT for 15 minutes, made basic withsatd. NaHCO₃ and extracted with EtoAc (2×). The combined organics werewashed with brine, dried over MgSO4, concentrated and purified viasilica gel chromatograph to give 1-(2-(dibenzylamino)ethyl)cyclopropanol(7.5 g, 88%) as a pale yellow oil. ¹H NMR (400 MHz, CDCl₃): δ 7.20-7.15(m, 8H), 7.12-7.07 (m, 2H), 3.45 (s, 4H), 2.61-2.59 (m, 2H), 1.57 (t,J=5.6 Hz, 2H), 0.36-0.33 (m, 2H), 0.30-0.17 (m, 2H).

A 0° C. solution of 1-(2-(dibenzylamino)ethyl)cyclopropanol (3 g, 10.6mmol) in THF (50 mL), under N₂, was treated portion-wise with NaH (60%,0.85 g, 21.3 mmol), stirred at 0° C. for 0.5 h, treated drop-wise withMel (1.82 g, 12.8 mmol), warmed to RT and stirred for 3 h. The mixturewas cooled to 0° C., quenched with satd. NH₄Cl and partiallyconcentrated. The residue was extracted with EtOAc (3×) and the combinedorganics were washed with brine, dried over Na₂SO₄, concentrated andpurified via silica gel chromatography to affordN,N-dibenzyl-2-(1-methoxycyclopropyl)ethanamine (1.2 g, 38%). ¹H NMR(400 MHz, CDCl₃): δ 7.39-7.21 (m, 10H), 3.60 (s, 4H), 3.12 (s, 3H), 2.65(t, J=8 Hz, 2H), 1.75 (t, J=8 Hz, 2H), 0.68-0.65 (m, 2H), 0.34-0.31 (m,2H).

A solution of N,N-dibenzyl-2-(1-methoxycyclopropyl)ethanamine (0.750 g,2.54 mmol) in EtOH (50 mL) was treated with 20% palladium hydroxide (50wt % with water, 0.357 g, 0.254 mmol) and hydrogenated (40 psi) for 4 h.The solids were removed via filtration through diatomaceous earth,rinsed well with MeOH and the filtrate carefully concentrated tonear-dryness to afford crude 2-(1-methoxycyclopropyl)ethanamine (361 mg,95% yield at 77% purity) as a yellow oil which was used without furtherpurification. ¹H NMR (400 MHz, DMSO-d₆): δ 5.41 (s, 2H), 3.13 (s, 3H),2.64 (t, J=7.3 Hz, 2H), 1.59 (t, J=7.3 Hz, 2H), 0.62-0.57 (m, 2H), 0.36(m, 2H).

A 0° C. solution of 2-(1-methoxycyclopropyl)ethanamine (0.361 g, 2.413mmol) in THF (15 mL) was treated drop-wise with 2-chloroethyl isocyanate(0.226 mL, 2.65 mmol), allowed to warm to RT, stirred overnight, thenconcentrated to dryness. The residue was treated with toluene andconcentrated to dryness (twice) to afford1-(2-chloroethyl)-3-(2-(1-methoxycyclopropyl)ethyl)urea (429 mg, 81%) asa yellow oil. MS (ESI) m/z: 221.1 (M+H⁺).

A −20° C. solution of1-(2-chloroethyl)-3-(2-(1-methoxycyclopropyl)ethyl)urea (0.429 g, 1.944mmol) in THF (10 mL), under argon, was treated with NaH (60% in mineraloil, 0.194 g, 4.86 mmol), and the mixture allowed to warm to RT as thecooling bath expired. The mixture was cooled to 0° C., quenched withsatd. NH₄Cl, warmed to RT, treated with brine, extracted with EtOAc (2×)and the combined organics were dried over MgSO₄, concentrated to drynessand purified via silica gel chromatography (MeOH/DCM) to afford1-(2-(1-methoxycyclopropyl)ethyl)imidazolidin-2-one (196 mg, 55%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.22 (s, 1H), 3.32-3.27(m, 2H), 3.19-3.17 (m, 2H), 3.14 (s, 3H), 3.12-3.11 (m, 2H), 1.67-1.65(m, 2H), 0.63-0.62 (m, 2H), 0.39-0.38 (m, 2H); MS (ESI) m/z: 185.1(M+H⁺).

Example B10

A 0° C. solution of 3-oxetanamine (0.200 g, 2.74 mmol) in THF (15 mL)was treated drop-wise with 2-chloroethyl isocyanate (0.257 mL, 3.01mmol), allowed to warm to RT as the cooling bath expired, thenconcentrated to dryness. The residue was treated with toluene andconcentrated to dryness (twice) to afford a white solid. The solid wasdissolved in THF (15 mL), cooled to −20° C., under Ar, treated with NaH(60% in mineral oil, 0.274 g, 6.84 mmol), allowed to warm to RT andstirred overnight. The mixture was cooled to 0° C., quenched with satd.NH₄Cl, warmed to RT, treated with brine and extracted with EtOAc (2×).The combined organics were dried over MgSO₄ and concentrated to dryness.The aqueous layer was treated with solid NaCl until saturated, extractedwith 1:1 EtOAc/THF (4×), then frozen and lyophilized. The lyophilizedsolid was stirred with EtOH for 1 h, the liquid decanted and the processrepeated. The EtOH extracts were combined with the EtOAc/THF extracts,concentrated to dryness, then treated with 10% MeOH/DCM and the solidsremoved via filtration. The filtrate was combined with the initial EtOAcextracts and purified via silica gel chromatography (MeOH/DCM) to afford1-(oxetan-3-yl)imidazolidin-2-one (270 mg, 69%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 6.52 (s, 1H), 4.86 (m, 1H), 4.71 (t, J=6.6 Hz,2H), 4.62 (t, J=7.2 Hz, 2H), 3.58 (m, 2H), 3.29 (m, 2H); MS (ESI) m/z:143.1 (M+H⁺).

Example B11

A 0° C. suspension of 2-(trifluoromethoxy)ethylamine hydrochloride(0.308 g, 1.861 mmol) in THF (10 mL) was treated with NaH (60% inmineral oil, 0.082 g, 2.047 mmol), stirred at 0° C. for 0.5 h, treateddrop-wise with 2-chloroethyl isocyanate (0.175 mL, 2.047 mmol), allowedto warm to RT and stirred overnight. The mixture was treated with EtOAc,the solids removed via filtration and the filtrate concentrated todryness to afford 1-(2-chloroethyl)-3-(2-(trifluoromethoxy)ethyl)urea(610 mg, 140%) containing EtOAc. ¹H NMR (400 MHz, DMSO-d₆): δ 6.29 (brs, 2H), 4.04-3.97 (m, 2H), 3.55 (t, J=6.2 Hz, 2H), 3.33-3.24 (m, 4H).

A −20° C. solution of1-(2-chloroethyl)-3-(2-(trifluoromethoxy)ethyl)urea (0.436 g, 1.858mmol) in THF (20 mL) was treated with NaH (60% in mineral oil, 0.082 g,2.044 mmol), warmed to RT and stirred overnight. The mixture was cooledto −20° C., treated with additional NaH (60% in mineral oil, 0.082 g,2.044 mmol) warmed to RT, stirred for 6 h, then quenched with satd.NH₄Cl. The mixture was extracted with EtOAc which was dried over MgSO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to afford 1-(2-(trifluoromethoxy)ethyl)imidazolidin-2-one(156 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.41 (s, 1H), 4.13 (t, J=5.3Hz, 2H), 3.35-3.34 (m, 4H), 3.22-3.20 (m, 2H); MS (ESI) m/z: 199.1(M+H⁺).

A 0° C. solution of phosgene (20 wt % in toluene, 0.497 mL, 0.945 mmol)in DCM (4 mL) was treated slowly with a solution of1-(2-(trifluoromethoxy)ethyl)imidazolidin-2-one (0.156 g, 0.787 mmol)and pyridine (0.127 mL, 1.575 mmol) in DCM (4 mL), stirred for 1 h at 0°C., then concentrated to dryness to afford2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carbonyl chloride(100% yield assumed). MS [quenched in MeOH] (ESI) m/z: 257.1 (M+H⁺).

Example B12

A solution of 4,4-difluorocyclohexanamine hydrochloride (0.800 g, 4.66mmol) in THF (20 mL) was treated with Na₂CO₃ (0.800 g, 7.55 mmol)followed by 1-chloro-2-isocyanatoethane (0.800 g, 7.58 mmol) and stirredat RT for 2 h. The mixture was cooled to 0° C., treated with NaH (60% inmineral oil, 0.300 g, 7.50 mmol), warmed to RT and stirred for 4 h. Themixture was poured into satd. NH₄Cl solution, the layers separated andthe aqueous layer extracted with DCM (3×). The combined organics werewashed with brine, dried over Na₂SO₄ and concentrated to dryness toafford 1-(4,4-difluorocyclohexyl)imidazolidin-2-one (624 mg, 66%) as awhite solid. MS (ESI) m/z: 205.1 (M+H⁺).

Example B13

A 0° C. suspension of (R)-(+)-tetrahydro-3-furylamine p-toluenesulfonatesalt (1.00 g, 3.86 mmol) in THF (40 mL) was treated with NaH (60% inmineral oil, 0.170 g, 4.24 mmol), stirred at 0° C. for 1.5 h, treatedwith 2-chloroethyl isocyanate (0.362 mL, 4.24 mmol) and stirred at RTovernight as the cooling bath expired. The mixture was treated withsatd. NH₄Cl and water, extracted with EtOAc (2×) and the combinedorganics were washed with brine (2×), dried over Na₂SO₄ and concentratedto dryness. The residue was treated with 1:1 EtOAc/Hex and the resultingsolid collected via filtration to afford(R)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea (522 mg, 70%). MS(ESI) m/z: 193.1 (M+H⁺).

A −20° C. solution of (R)-1-(2-chloroethyl)-3-(tetrahydrofuran-3-yl)urea(0.522 g, 2.71 mmol) in THF (30 mL) was treated with NaH (60% in mineraloil, 0.130 g, 3.25 mmol) and the mixture stirred at RT overnight as thecooling bath expired. The mixture was treated with satd. NH₄Cl, driedover MgSO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford(R)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (280 mg, 66%). MS (ESI)m/z: 157.1 (M+H⁺).

A 0° C. solution of phosgene (20% in toluene, 1.132 mL, 2.151 mmol) inDCM (9 mL) was treated slowly with a solution of(R)-1-(tetrahydrofuran-3-yl)imidazolidin-2-one (0.28 g, 1.793 mmol) andpyridine (0.290 mL, 3.59 mmol) in DCM (9 mL) and stirred at 0° C. for 45min. The mixture was concentrated to dryness to afford crude(R)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carbonyl chloride(100% yield assumed) which was used without further purification.

Example B14

A 0° C. solution of cyclopentylamine (4.63 mL, 47.0 mmol) in THF (235mL) was treated drop-wise with 2-chloroethyl isocyanate (4.41 mL, 51.7mmol) which was allowed to warm to RT, then concentrated to dryness. Thesolid was suspended in toluene and concentrated again to dryness toafford 1-(2-chloroethyl)-3-cyclopentylurea (8.95 g, 100%) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 6.01 (d, J=7.3 Hz, 1H),5.91 (t, J=5.8 Hz, 1H), 3.85-3.76 (m, 1H), 3.54 (t, J=6.2 Hz, 2H), 3.27(q, J=6.1 Hz, 2H), 1.78-1.69 (m, 2H), 1.62-1.53 (m, 2H), 1.51-1.42 (m,2H), 1.30-1.20 (m, 2H); MS (ESI) m/z: 191.1 (M+H⁺).

A −20° C. solution of 1-(2-chloroethyl)-3-cyclopentylurea (8.5 g, 44.6mmol) in THF (446 mL), under Ar, was treated with NaH (60% in mineraloil, 4.46 g, 111 mmol), stirred at −10° C. for 1 h, 0° C. for 1 h, thenRT for 3 h. The mixture was cooled to 0° C., treated with 50% satd.NH₄Cl, the layers separated and the aqueous layer extracted with EtOAc(3×). The combined organics were dried over Na₂SO₄ and concentrated todryness. The material was suspended in Et₂O, the solids removed viafiltration and the filtrate concentrated to dryness. The resultingmaterial was dissolved in DCM, treated drop-wise with hexane untilsolids formed and the solids were collected via filtration and dried toafford 1-cyclopentylimidazolidin-2-one (4.3 g, 63%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 6.16 (s, 1H), 4.07-3.98 (m, 1H), 3.28-3.22 (m,2H), 3.19-3.14 (m, 2H), 1.66-1.55 (m, 4H), 1.52-1.41 (m, 4H); MS (ESI)m/z: 155.1 (M+H⁺).

Example B15

A solution of 2-methylallylamine (0.156 g, 2.197 mmol) in dioxane (5 mL)was treated with DBU (0.030 mL, 0.200 mmol) and cyclohexyl isocyanate(0.25 g, 1.997 mmol) and heated at 60° C. overnight. The mixture wascooled to RT, treated with water, extracted with EtOAc (2×) and thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford 1-cyclohexyl-3-(2-methylallyl)urea(340 mg, 87%). ¹H NMR (400 MHz, DMSO-d₆): δ 5.80 (m, 1H), 5.72 (d, J=8.0Hz, 1H), 4.72 (m, 1H), 4.68 (m, 1H), 3.50 (d, J=5.3 Hz, 2H), 3.30 (m,1H), 1.70 (m, 2H), 1.61 (s, 3H), 1.60 (m, 1H), 1.48 (m, 1H), 1.27 (m,2H), 1.13 (m, 4H); MS (ESI) m/z: 197.2 (M+H⁺).

A solution of 1-cyclohexyl-3-(2-methylallyl)urea (0.34 g, 1.732 mmol) inTFA (3 mL) was stirred at RT overnight, then concentrated to dryness.The residue treated was treated with satd. NaHCO₃, extracted with EtOAc(2×) and the combined organics were washed with brine, dried over Na₂SO₄and concentrated to dryness to afford crude1-cyclohexyl-5,5-dimethylimidazolidin-2-one (100% yield assumed) whichwas used without further purification. MS (ESI) m/z: 197.2 (M+H⁺).

A 0° C. solution of phosgene (15% in toluene, 1.854 mL, 2.60 mmol) inDCM (10 mL) was treated drop-wise with a solution of1-cyclohexyl-5,5-dimethylimidazolidin-2-one (0.34 g, 1.732 mmol) andpyridine (0.28 mL) in DCM (5 mL), stirred at 0° C. for 0.5 h, thenconcentrated to dryness to afford crude3-cyclohexyl-4,4-dimethyl-2-oxoimidazolidine-1-carbonyl chloride (0.45g, 100%) which was used without further purification.

Example B16

A solution of t-butylamine (6.00 g, 82 mmol) in MeCN (120 mL) wastreated with 2-chloroethylisocyanate (9.00 g, 85 mmol), stirred at RTfor 1 h, and the resulting solid was collected via filtration to afford1-(tert-butyl)-3-(2-chloroethyl)urea (12.2 g, 83%) as a white solid. ¹HNMR (400 MHz, DMSO-d₆): δ 5.89 (t, J=5.9 Hz, 1H), 5.82 (s, 1H), 3.53 (t,J=6.2 Hz, 2H), 3.24 (q, J=6.1 Hz, 2H), 1.19 (s, 9H); MS (ESI) m/z: 179.1(M+H⁺).

A 0° C. solution of 1-(tert-butyl)-3-(2-chloroethyl)urea (2.00 g, 11.19mmol) in THF (20 mL) was treated with NaH (60% in mineral oil, 0.800 g,33.3 mmol), stirred at RT for 1 h, then heated at 65° C. overnight. Themixture was cooled to RT, concentrated to dryness, treated with satd.NH₄Cl, extracted with EtOAc (3×) and the combined organics were driedover Na₂SO₄ and concentrated to dryness to afford1-(tert-butyl)imidazolidin-2-one (1.19 g, 75%). MS (ESI) m/z: 143.1(M+H⁺).

Example B17

A solution of isopropylamine (3.00 g, 50.8 mmol) in MeCN (30 mL) wastreated with 2-chloroethylisocyanate (6.00 g, 56.9 mmol), stirred at RTfor 1 h and the resulting solid collected via filtration to afford1-(2-chloroethyl)-3-isopropylurea (6.12 g, 73%) as a white solid. ¹H NMR(400 MHz, DMSO-d₆): δ 5.96 (t, J=5.9 Hz, 1H), 5.87 (d, J=7.7 Hz, 1H),3.62 (m, 1H), 3.53 (t, J=6.3 Hz, 2H), 3.25 (m, 2H), 0.99 (d, J=6.5 Hz,6H); MS (ESI) m/z: 165.1 (M+H⁺).

A 0° C. suspension of 1-(2-chloroethyl)-3-isopropylurea (6.00 g, 36.4mmol) in THF (60 mL) was treated with NaH (60% in mineral oil, 2.50 g,104 mmol) and stirred at RT overnight. The mixture was concentrated todryness, treated with satd. NH₄Cl, extracted with EtOAc (3×) and thecombined organics were dried over Na₂SO₄ and concentrated to dryness toafford 1-isopropylimidazolidin-2-one (3.21 g, 69%) as a waxy solid. MS(ESI) m/z: 129.1 (M+H⁺).

Example B18

A mixture of ethylamine (2.0M in THF, 2.369 mL, 4.74 mmol) andchloroethylisocyanate (0.50 g, 4.74 mmol) was stirred at RT for 2 h,concentrated to dryness and treated with MeCN. The solid was collectedvia filtration and dried to afford 1-(2-chloroethyl)-3-ethylurea (460mg, 65%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.05 (s, 1H), 5.96 (s, 1H), 3.54(t, J=6.3 Hz, 2H), 3.30-3.23 (m, 2H), 3.02-2.93 (m, 2H), 0.96 (t, J=7.2Hz, 3H); MS (ESI) m/z: 151.1 (M+H⁺).

A 5° C. solution of 1-(2-chloroethyl)-3-ethylurea (0.46 g, 3.05 mmol) inTHF (20 mL), under Ar, was treated with NaH (60% in mineral oil, 0.134g, 3.36 mmol), warmed to RT and stirred overnight. The mixture wastreated with satd. NH₄Cl, extracted with EtOAc (2×) and the combinedorganics were washed with brine, dried over Na₂SO₄ and concentrated todryness to afford crude 1-ethylimidazolidin-2-one (190 mg, 55%) whichwas used without further purification. MS (ESI) m/z: 115.1 (M+H⁺).

Example B19

A solution of 2,2,2-trifluoroethanamine (0.469 g, 4.74 mmol) andchloroethylisocyanate (0.50 g, 4.74 mmol) in THF (10 mL) was stirred atRT for 2 h, then concentrated to dryness. The residue was treated withDCM, concentrated to dryness and dried to afford1-(2-chloroethyl)-3-(2,2,2-trifluoroethyl)urea (910 mg, 94%). ¹H NMR(400 MHz, DMSO-d₆): δ 6.67 (t, J=6.5 Hz, 1H), 6.41 (m, 1H), 3.80 (m,2H), 3.57 (t, J=6.2 Hz, 2H), 3.32 (m, 2H); MS (ESI) m/z: 205.0 (M+H⁺).

A 5° C. solution of 1-(2-chloroethyl)-3-(2,2,2-trifluoroethyl)urea (0.91g, 4.45 mmol) in THF (20 mL), under Ar, was treated with NaH (60% inmineral oil, 0.196 g, 4.89 mmol), warmed to RT and stirred for 5 h. Themixture was treated with satd. NH₄Cl, extracted with EtOAc (3×) and thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford1-(2,2,2-trifluoroethyl)imidazolidin-2-one (730 mg, 98%). ¹H NMR (400MHz, DMSO-d₆): δ 6.76 (s, 1H), 3.81 (q, J=9.9 Hz, 2H), 3.43 (m, 2H),3.28 (m, 2H); MS (ESI) m/z: 169.0 (M+H⁺).

Example B20

A solution of cyclopropanamine (0.541 g, 9.48 mmol) in THF (10 mL) wastreated with chloroethylisocyanate (1.0 g, 9.48 mmol), stirred at RT for2 h, then concentrated to dryness and treated with MeCN. The resultingsolid was collected via filtration and dried to afford1-(2-chloroethyl)-3-cyclopropylurea (1.31 g, 85%). ¹H NMR (400 MHz,DMSO-d₆): δ 6.28 (s, 1H), 6.12 (br s, 1H), 3.55 (t, J=6.4 Hz, 2H), 3.30(m, 2H), 2.36 (m, 1H), 0.55 (m, 2H), 0.31 (m, 2H); MS (ESI) m/z: 162.9(M+H⁺).

A 0° C. solution of 1-(2-chloroethyl)-3-cyclopropylurea (1.31 g, 8.06mmol) in THF (40 mL) was treated with NaH (60% in mineral oil, 0.387 g,9.67 mmol), stirred for 10 minutes, then warmed to RT and stirred for 6h. The mixture was treated with satd. NH₄Cl, the solids removed viafiltration and washed with EtOAc. The filtrate was washed with brine,dried over Na₂SO₄ and concentrated to dryness to afford crude1-cyclopropylimidazolidin-2-one (760 mg, 75%) which was used withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆): δ 6.27 (s, 1H), 3.25(m, 2H), 3.14 (m, 2H), 2.29 (m, 1H), 0.53 (m, 4H).

Example C1

A 0° C. mixture of Example A5 (1 g, 4.51 mmol) and pyridine (1.1 mL,13.6 mmol) in DCM (25 mL) was treated with a solution of Example B2(1.680 g, 7.22 mmol) in DCM (8 mL), warmed to RT and stirred 45 min. Themixture was concentrated to dryness, the residue treated with DCM andEt2O, sonicated and the resulting solid collected via filtration. Thesolid was dissolved in DCM, washed with water, the aqueous layerback-extracted with DCM (3×) and the combined organics were dried overNa₂SO₄ and concentrated to dryness to affordN-(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(2.24 g, 119%) which was used without further purification. MS (ESI)m/z: 418.1 (M+H⁺).

Example C2

A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.5 g, 7.73 mmol) K₂CO₃ (1.068 g, 7.73 mmol) and methyl iodide-d₃(2.241 g, 15.46 mmol) in MeCN (15.5 mL) was heated at 60° C. overnight.The solids were removed via filtration, washed with acetone and thefiltrate concentrated to dryness to afford crude4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-(trideuteromethyl)-1H-pyrazole(877 mg, 54%) which was used without further purification. MS (ESI) m/z:212.2 (M+H⁺).

Example C3

Phosgene (20% in toluene, 2.62 g, 5.3 mmol) was treated with a solutionof Example B1 (0.27 g, 1.59 mmol) and pyridine (0.43 mL, 5.3 mmol) inDCM (5 mL), stirred for 15 min, then concentrated to dryness. Theresidue was dissolved in DCM (5 mL), treated with a solution of ExampleA7 (0.25 g, 1.06 mmol) and TEA (0.74 mL, 5.3 mmol) in DCM (5 mL) andstirred at RT for 1 h. The mixture was treated with satd. NaHCO₃,extracted with EtOAc (2×) and the combined organics were washed withbrine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (EtOAc/Hex) to affordN-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(0.24 g, 52%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 8.27 (d,J=5.8 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.02 (d,J=2.3 Hz, 1H), 6.92 (dd, J=5.8, 2.3 Hz, 1H), 3.94-3.84 (m, 5H),3.48-3.35 (m, 4H), 2.21 (s, 3H), 1.74-1.66 (m, 2H), 1.60 (d, J=12.5 Hz,2H); MS (ESI) m/z: 432.1 (M+H⁺).

Example C4

A solution of 3-methoxy-3-methylbutan-1-ol (2.50 g, 21.16 mmol) in DCM(30 mL) was treated with p-toluene sulfonyl chloride (5.00 g, 26.2 mmol)followed by TEA (4.28 g, 42.3 mmol) and stirred at RT for 3 h. Themixture was washed with satd. NaHCO₃, then brine, dried over Na₂SO₄ andconcentrated to dryness to afford 3-methoxy-3-methylbutyl4-methylbenzenesulfonate (2.84 g, 49%). ¹H NMR (400 MHz, DMSO-d₆): δ7.76 (d, J=8.2 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 4.03 (t, J=7.2 Hz, 2H),2.96 (s, 3H), 2.38 (s, 3H), 1.75 (t, J=7.2 Hz, 2H), 1.01 (s, 6H); MS(ESI) m/z: 295.0 (M+Na⁺).

Example C5

A 0° C. mixture of Example A7 (0.350 g, 1.485 mmol) and pyridine (0.251mL, 3.12 mmol) in DCM (10 mL) was treated with a solution of Example B4(0.368 g, 1.782 mmol) in DCM (5 mL) and stirred at RT overnight. Themixture was treated with satd. NaHCO₃, extracted with DCM (2×) and thecombined organics were dried over Na₂SO₄, concentrated to dryness andpurified twice via silica gel chromatography (MeOH/DCM) to affordN-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide(487 mg, 81%) as a yellow oil. MS (ESI) m/z: 406.1 (M+H⁺).

Example C6

A −78° C. solution of 2-methylthiazole (2 g, 20.17 mmol) in THF (50 mL)was treated drop-wise with n-butyllithium (2.5 M in Hex, 10.49 mL, 26.2mmol), stirred for 1 h, treated drop-wise with a solution of tributyltinchloride (7.11 mL, 26.2 mmol) in THF (25 mL) and stirred for anadditional 1 h at −78° C. The mixture was allowed to warm to RT, stirredfor 1 h, treated slowly with ice-cold satd. NaHCO₃ (20 mL) and quicklyextracted with Et₂O (3×). The combined organics were washed with brine,dried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to afford2-methyl-5-(tributylstannyl)thiazole (6.67 g, 85%). ¹H NMR (400 MHz,DMSO-d₆): δ 7.55 (s, 1H), 2.67 (s, 3H), 1.54-1.45 (m, 6H), 1.30-1.23 (m,6H), 1.09-1.04 (m, 6H), 0.83 (t, J=7.3 Hz, 9H).

Example C7

A mixture of 4-(4-bromo-phenyl)-1-methyl-piperidine (1.0 g, 3.93 mmol),bis(pinacolato)diboron (1.499 g, 5.90 mmol), K₂CO₃ (1.158 g, 11.80mmol), dppf (0.218 g, 0.393 mmol) and Pd₂(dba)₃ (0.180 g, 0.197 mmol) indioxane (10 mL) was sparged with Ar and heated at 85° C. overnight. Themixture was treated with additional bis(pinacolato)diboron (0.5 g), dppf(0.050 g) and Pd₂(dba)₃ (0.04 g), sparged with Ar and heated at 105° C.for 5 h. The mixture was cooled to RT, diluted with EtOAc and the solidsremoved via filtration through diatomaceous earth, washed with EtOAc andthe filtrate concentrated to dryness to afford1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperidine(100% yield assumed) which was used without further purification. MS(ESI) m/z: 302.2 (M+H⁺).

Example C8

A 0° C. suspension of Example A21 (0.145 g, 0.533 mmol) and TEA (0.223mL, 1.598 mmol) in DCM (2.5 mL) was treated with a thin suspension ofcrude Example B2 (0.198 g, 0.852 mmol) in DCM (2.5 mL), warmed to RT andstirred for 0.5 h. The mixture was washed with water (3×), dried overMgSO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to affordN-(5-chloro-4-((2-chloropyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(202 mg, 81%) as a pale pink solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.93(d, J=2.7 Hz, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.30 (d, J=5.8 Hz, 1H), 7.64(d, J=11.2 Hz, 1H), 7.09 (d, J=2.3 Hz, 1H), 6.97 (dd, J=5.8, 2.3 Hz,1H), 3.91-3.88 (m, 3H), 3.80 (m, 2H), 3.47 (t, J=8.2 Hz, 2H), 3.37 (t,J=11.6 Hz, 2H), 1.71 (m, 2H), 1.59 (m, 2H); MS (ESI) m/z: 469.1 (M+H+).

Example C9

A 0° C. solution of triphosgene (0.330 g, 1.112 mmol) in MeCN (5 mL) wastreated with a solution of imidazolidin-2-one (0.200 g, 2.323 mmol) MeCN(5 mL), stirred at RT for 10 min, added to a suspension of Example A22(0.400 g, 1.255 mmol) in MeCN (5 mL) and heated at 50° C. for 1 h. Thesolids were collected via filtration to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxoimidazolidine-1-carboxamide(424 mg, 78%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.00 (d, J=2.7 Hz, 1H),8.63 (s, 1H), 8.48 (m, 2H), 8.32 (s, 1H), 8.04 (s, 1H), 7.68 (d, J=11.1Hz, 1H), 7.59 (s, 1H), 7.06 (br s, 1H), 3.90 (m, 5H), 3.40 (m, 2H); MS(ESI) m/z: (M+H⁺): 431.1.

Example 1

A 0° C. solution of Example A2 (6.4 g, 23.94 mmol) and pyridine (6 mL,74.2 mmol) in DCM (150 mL) was treated with a solution of Example B2(8.36 g, 35.9 mmol) in DCM (10 mL), stirred at 0° C. for 5 min, warmedto RT and stirred for 1.5 h. The mixture was diluted with water, stirredfor 15 min, and the layers separated. The organic layer was washed withwater and the combined aqueous layers were extracted with DCM (4×). Thecombined organics were dried over Na2SO4, concentrated to dryness,treated with MeOH and concentrated again to dryness. The residue wasdissolved in DCM, sonicated, treated with MTBE, sonicated and theresulting solid collected via filtration. The solid was treated withEt₂O, sonicated and again collected via filtration to affordN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(8.93 g, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 8.36 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07 (dd, J=9.0,0.7 Hz, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22(d, J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.5 Hz, 1H), 3.93-3.87 (m, 3H), 3.84(s, 3H), 3.83-3.77 (m, 2H), 3.49-3.43 (m, 2H) 3.42-3.34 (m, 2H),1.78-1.64 (m, 2H), 1.59 (m, 2H); MS (ESI) m/z: 464.2 (M+H⁺).

Example 2

A solution of phosgene (15% in toluene, 1.77 mL, 2.52 mmol) was cooledto 0° C. To this was added, drop-wise over 15 min, a solution ofpyridine (0.226 mL, 2.80 mmol) and Example B17 (158 mg, 1.23 mmol) inDCM (2 mL). The reaction mixture was stirred for 1 h at RT and wasevaporated at reduced pressure to near dryness. This residue was thentreated with DCM (2 mL) and added drop-wise to a 0° C. mixture (not asolution) of Example A27 (150 mg, 0.559 mmol) and pyridine (0.22 mL,2.80 mmol) in DCM (2 mL). The reaction mixture was stirred at 0° C. for15 min, then at RT for 20 h. The mixture was treated with half-saturatedsodium bicarbonate (15 mL) and EtOAc (25 mL) and warmed gently todissolve most solids. The mixture was filtered and the organic phase ofthe filtrate was washed with brine (25 mL), dried over sodium sulfateand evaporated at reduced pressure. Purification by reverse phase silicagel chromatography (5-45% MeCN/water (0.1% TFA)) provided3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-yl)-2-oxoimidazolidine-1-carboxamide(56 mg, 21%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.30 (s, 1H), 8.66 (s, 2H),8.39 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98 (s, 1H), 7.28 (d, J=2.5 Hz,1H), 6.81 (dd, J=5.7, 2.5 Hz, 1H), 4.03-4.02 (m, 1H), 3.84 (s, 3H), 3.79(t, J=8.2 Hz, 2H), 3.41 (t, J=8.2 Hz, 2H), 1.13 (d, J=6.7 Hz, 6H); MS(ESI) m/z: 423.2 (M+H⁺).

Example 3

A solution of Example B1 (0.1 g, 0.6 mmol) and pyridine (0.07 g, 0.9mmol) in DCM (3 mL) was added to phosgene (20% in toluene, 0.75 g, 1.51mmol), under Ar, stirred for 15 min, then concentrated to dryness. Theresidue was dissolved in DCM (5 mL), treated with a solution of ExampleA4 (0.085 g, 0.3 mmol) and TEA (0.2 mL, 1.5 mmol) in DCM (3 mL) andstirred at RT for 0.5 h. The mixture was treated with satd. NaHCO₃,extracted with EtOAc (2×) and the combined organics were washed withbrine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/DCM) to affordN-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(110 mg, 76%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s, 1H), 8.35-8.32 (m,1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.61 (d, J=8.8Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.5 Hz, 1 H),3.90-3.75 (m, 8H), 3.44-3.40 (m, 4H), 2.24 (s, 3H), 1.72 (m, 2H), 1.60(dd, J=12.4, 4.0 Hz, 2H); MS (ESI) m/z: 478.2 (M+H⁺).

Example 4

A mixture of Example C1 (0.15 g, 0.40 mmol),1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.088 g, 0.40 mmol), and K₂CO₃ (0.2 g, 1.44 mmol) in 4:1 dioxane/water(5 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (0.040 g, 0.036mmol), sparged again with Ar and heated at 80° C. overnight. The mixturewas cooled to RT, treated with brine, extracted with EtOAc (2×) and thecombined organics were dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM). The material wastreated with Et₂O, allowed to stand at RT and the resulting solidcollected via filtration to affordN-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(137 mg, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 8.37 (d,J=5.7 Hz, 1H), 8.30 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07 (d, J=9.0 Hz,1H), 7.97 (s, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H),6.69 (dd, J=5.7, 2.4 Hz, 1H), 4.13 (q, J=7.3 Hz, 2H), 3.86 (m, 5H), 3.40(m, 4H), 1.71 (m, 2H), 1.59 (m, 2H), 1.37 (t, J=7.3 Hz, 3H); MS (ESI)m/z: 478.2 (M+H⁺).

Example 5

A mixture of Example C1 (0.15 g, 0.359 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.077 g,0.395 mmol), and K₂CO₃ (0.198 g, 1.436 mmol) in 4:1 dioxane/water (5 mL)was sparged with Ar, treated with Pd(PPh₃)₄ (0.041 g, 0.036 mmol),sparged again with Ar and heated at 80° C. overnight. The mixture wascooled to RT, treated with brine, extracted with EtOAc (2×) and thecombined organics were dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM). The material wastreated with Et₂O, allowed to stand at RT and the resulting solidcollected via filtration to affordN-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(80 mg, 48%). ¹H NMR (400 MHz, DMSO-d₆): δ 13.04 (s, 1H), 10.96 (s, 1H),8.37 (d, J=5.7 Hz, 1H), 8.32 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07 (d,J=9.0 Hz, 1H), 8.02 (s, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.32 (d,J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.91-3.80 (m, 5H), 3.40 (m,4H), 1.71 (m, 2H), 1.59 (m, 2H); MS (ESI) m/z: 450.2 (M+H⁺).

Example 6

A suspension of Example C1 (0.350 g, 0.838 mmol), Example C2 (0.212 g,1.005 mmol) and K₂CO₃ (0.463 g, 3.35 mmol) in dioxane (6.7 mL) and water(1.7 mL) was sparged with Ar for 0.5 h, treated with Pd(PPh₃)₄ (0.145 g,0.126 mmol), sparged again with Ar and heated at 80° C. overnight.Reaction mixture had concentrated to dryness; it was cooled to RT,re-suspended in dioxane (6.7 mL) and water (1.7 mL), sparged with Ar,treated with Pd(PPh₃)₄ (0.050 g, 0.043 mmol), sparged again with Ar andheated at 80° C. for 24 h. The mixture was cooled to RT, treated withsatd. NaHCO₃, extracted with EtOAc (3×) and the combined organics weredried over Na₂SO₄, concentrated to dryness and purified twice via silicagel chromatography (MeOH/DCM) to afford2-oxo-3-(tetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)imidazolidine-1-carboxamide(41 mg, 10.5%) as a beige solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s,1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (d, J=0.8 Hz, 1H), 8.23 (dd, J=2.9,0.7 Hz, 1H), 8.07 (dd, J=9.0, 0.7 Hz, 1H), 7.96 (d, J=0.8 Hz, 1H), 7.72(dd, J=9.0, 2.9 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4Hz, 1H), 3.93-3.77 (m, 5H), 3.49-3.35 (m, 4H), 1.77-1.65 (m, 2H),1.63-1.56 (m, 2H); MS (ESI) m/z: 467.2 (M+H⁺).

Example 7

A solution of Example A5 (0.60 g, 2.70 mmol) in THF (10 mL) was treatedwith di-tert-butyl dicarbonate (0.65 g, 3.0 mmol) and DMAP (0.066 g,0.54 mmol) and stirred at RT overnight. The mixture was diluted with 30%EtOAc/Hex, stirred for 10 and the solid collected via filtration anddried. The filtrate was concentrated to dryness, purified via silica gelchromatography (EtOAc/Hex) and combined with the above-isolated solid toafford tert-butyl (5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamate(703 mg, 81% yield). MS (ESI) m/z: 322.1 (M+H⁺).

A solution of tert-butyl(5-((2-chloropyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.70 g, 2.18 mmol)in DMF (5 mL) was sparged with Ar, treated with ethynyltrimethylsilane(0.64 g, 6.55 mmol), TEA (1 mL), copper(I)iodide (0.042 g, 0.22 mmol)and trans dichlorobis(triphenylphosphine)palladium(0) (0.15 g, 0.22mmol) and heated at 75° C., under Ar, overnight. The mixture was cooledto RT, diluted with EtOAc, the solids removed via filtration throughdiatomaceous earth and washed with EtOAc and water. The layers of thefiltrate were separated, the aqueous layer extracted with EtOAc (2×) andthe combined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness. The material was dissolved in MeOH (20 mL),treated with K₂CO₃ (0.7 g), stirred at RT for 2 h, then concentrated todryness. The residue was treated with EtOAc, sonicated, the solidsremoved via filtration through diatomaceous earth, washed with EtOAc andthe filtrate concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to afford tert-butyl(5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.29 g, 43%). ¹HNMR (400 MHz, DMSO-d₆): δ 9.96 (s, 1H), 8.41 (d, J=5.6 Hz, 1H), 8.18 (d,J=2.8 Hz, 1H), 7.88 (d, J=9.2 Hz, 1H), 7.66 (m, 1H), 7.07 (d, J=2.4 Hz,1H), 6.95 (m, 1H), 4.34 (s, 1H), 1.46 (s, 9H); MS (ESI) m/z: 312.1(M+H⁺).

A solution of NCS (0.36 g, 2.70 mmol) in DMF (2 mL) was treated withacetaldoxime (0.16 g, 2.70 mmol), stirred at RT for 0.5 h, added to asolution of tert-butyl(5-((2-ethynylpyridin-4-yl)oxy)pyridin-2-yl)carbamate (0.28 g, 0.90mmol) and TEA (2 mL) in DMF (2 mL) and heated at 60° C. for 2 h. Themixture was treated with water, extracted with EtOAc (3×) and thecombined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to afford tert-butyl(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamate(250 mg, 75%). MS (ESI) m/z: 369.1 (M+H⁺).

A solution of tert-butyl(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamate(0.30 g, 0.84 mmol) in THF (5 mL) was treated with HCl (3 M, 2.8 mL, 8.4mmol), heated at 55° C. for 4 h, then cooled to RT and concentrated todryness. The residue was treated with NaHCO3, EtOAc and water, thelayers separated and the aqueous layer extracted with EtOAc (2×). Thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.24 g,106%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.52 (d, J=5.6 Hz, 1H), 7.84 (br s,1H), 7.32 (m, 2H), 6.95 (m, 2H), 6.53 (d, J=9.2 Hz, 1H), 6.07 (br s,2H), 2.28 (s, 3H); MS (ESI) m/z: 269.1 (M+H⁺).

A 0° C. mixture of5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (0.052 g,0.194 mmol) and TEA (0.059 g, 0.582 mmol) in DCM (3 mL) was treated witha suspension of crude Example B2 (0.090 g, 0.388 mmol) in DCM (2 mL),warmed to RT and stirred. The mixture was re-cooled to 0° C., treatedwith additional Example B2 (68 mg), warmed to RT and stirred overnight.The mixture was concentrated to dryness, purified via silica gelchromatography (MeOH/DCM), treated with Et₂O, and the resulting solidcollected via filtration to affordN-(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(45 mg, 49%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.99 (s, 1H), 8.57 (d, J=5.7Hz, 1H), 8.28 (dd, J=2.9, 0.7 Hz, 1H), 8.09 (m, 1H), 7.78 (dd, J=9.0,2.9 Hz, 1H), 7.41 (d, J=2.5 Hz, 1H), 7.04 (dd, J=5.7, 2.5 Hz, 1H), 6.98(s, 1H), 3.94-3.86 (m, 3H), 3.83-3.80 (m, 2H), 3.50-3.35 (m, 4H), 2.28(s, 3H), 1.78-1.65 (m, 2H), 1.64-1.55 (m, 2H); MS (ESI) m/z: 465.2(M+H⁺).

Example 8

A −10° C. suspension of NaH (60% in mineral oil, 0.73 g, 18.2 mmol) inDMA (15 mL) was treated with 6-aminopyridin-3-ol (1.0 g, 9.1 mmol),stirred for 0.5 h, treated drop-wise with a solution of4,6-dichloropyrimidine (2.03 g, 13.6 mmol) in DMA (10 mL), warmed to RTand stirred for 2 h. The mixture was treated with water, extracted withDCM (3×) and the combined organics were washed with 5% LiCl, then brine,dried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc) to afford5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (1.0 g, 50%). ¹H NMR (400MHz, DMSO-d₆): δ 8.62 (d, 1H), 7.79 (d, 1H), 7.33-7.26 (m, 2H), 6.48 (d,1H), 6.00 (s, 2H); MS (ESI) m/z: 223.0 (M+H⁺).

A mixture of 5-((6-chloropyrimidin-4-yl)oxy)pyridin-2-amine (0.50 g,2.25 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(0.47 g, 2.25 mmol), and Cs₂CO₃ (1.46 g, 4.49 mmol) in 5:1 dioxane/water(6 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (0.26 g, 0.23 mmol),sparged again with Ar and heated at 90° C. overnight. The mixture wascooled to RT, the solids removed via filtration, washed with dioxane andthe filtrate concentrated to dryness. The residue was treated withwater, extracted with EtOAc, washed with brine, dried over Na₂SO₄, andconcentrated to dryness. The material was treated with EtOAc and theresulting solid collected via filtration to afford5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.41g, 68%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.60 (d, 1H), 8.44 (s, 1H), 8.12(s, 1H), 7.78 (d, 1H), 7.28 (m, 2H), 6.48 (d, 1H), 5.94 (s, 2H), 3.88(s, 3H); MS (ESI) m/z: 269.1 (M+H⁺).

A 0° C. solution of Example B2 (0.14 g, 0.60 mmol) in DCM (3 mL) wastreated drop-wise with a solution of5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-amine (0.08g, 0.30 mmol) and TEA (0.1 mL, 0.9 mmol) in DCM (2 mL), warmed to RT andstirred for 2 h. The mixture was concentrated to dryness, purified viasilica gel chromatography (MeOH/DCM), treated with Et₂O and theresulting solid collected via filtration to affordN-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(93 mg, 67%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.62 (d, J=1.1Hz, 1H), 8.46 (s, 1H), 8.22 (m, 1H), 8.16 (d, J=0.7 Hz, 1H), 8.04 (d,J=9.0 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.42 (d, J=1.1 Hz, 1H),3.89 (s, 3H), 4.00-3.70 (m, 5H), 3.42-3.39 (m, 4H), 1.76-1.65 (m, 2H),1.59 (m, 2H); MS (ESI) m/z: 465.2 (M+H⁺).

Example 9

A solution of Example C3 (0.12 g, 0.28 mmol) in dioxane (4 mL) wassparged with Ar, treated with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.08 g,0.42 mmol), a solution of K₂CO₃ (0.077 g, 0.55 mmol) in water (1 mL) andPd(PPh₃)₄ (0.032 g, 0.03 mmol) and heated at 90° C. overnight. Themixture was cooled to RT, diluted with water, extracted with EtOAc (2×)and the combined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to affordN-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(72 mg, 56%). ¹H NMR (400 MHz, DMSO-d₆): δ 13.05 (br s, 1H), 10.89 (s,1H), 8.35 (d, J=5.7 Hz, 1H), 8.31 (brs, 1H), 8.03 (s, 1H), 7.89 (d,J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.28 (d, J=2.4 Hz, 1H), 6.56 (dd,J=5.7, 2.4 Hz, 1H), 3.95-3.77 (m, 5H), 3.43-3.39 (m, 4H), 2.24 (s, 3H),1.71-1.70 (m, 2H), 1.60 (d, J=12.4 Hz, 2H); MS (ESI) m/z: 464.2 (M+H⁺).

Example 10

A 0° C. mixture of Example A2 (0.150 g, 0.561 mmol) and pyridine (0.15mL, 1.862 mmol) in DCM (5 mL) was treated with a solution of Example B4(0.232 g, 1.122 mmol) in THF (5 mL), warmed to RT and stirred overnight.The mixture was concentrated to dryness, purified via silica gelchromatography (MeOH/DCM) and the resulting material was treated withEt₂O and the solid collected via filtration to afford3-(2-methoxyethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(151 mg, 62%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (s,1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.83-3.80 (m,2H), 3.53-3.46 (m, 4H), 3.41-3.36 (m, 2H), 3.26 (s, 3H); MS (ESI) m/z:438.1 (M+H⁺).

Example 11

A 0° C. solution of phosgene (20% in toluene, 0.7 mL, 6.62 mmol) in DCM(13 mL) was treated drop-wise with a solution of pyridine (0.25 mL, 3.09mmol) and Example B5 (0.203 g, 1.283 mmol) in DCM (10 mL) allowed towarm to RT and stirred for 0.5 h. The mixture was concentrated todryness to afford crude3-(3-methoxypropyl)-2-oxoimidazolidine-1-carbonyl chloride (100% yieldassumed) which was used without further purification. MS (quenched intobenzyl amine) (ESI) m/z: 292.1 (M+72+H⁺).

A 0° C. mixture of Example A2 (0.160 g, 0.599 mmol) and pyridine (0.15mL, 1.862 mmol) in DCM (5 mL) was treated with a solution of3-(3-methoxypropyl)-2-oxoimidazolidine-1-carbonyl chloride (0.264 g,1.197 mmol) in THF (5 mL), warmed to RT and stirred overnight. Themixture was treated with water, stirred for 10 min, the layers separatedand the aqueous layer extracted with DCM (2×). The combined organicswere dried over Na₂SO₄, concentrated to dryness, purified via silica gelchromatography (MeOH/DCM) and the resulting material was treated withEt₂O and the solid collected via filtration to afford3-(3-methoxypropyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(155 mg, 57%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.97 (s,1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.81-3.79 (m,2H), 3.46 (m, 2H), 3.34 (m, 2H), 3.27 (m, 2H), 3.22 (s, 3H), 1.77-1.69(m, 2H); MS (ESI) m/z: 452.2 (M+H⁺).

Example 12

A 0° C. solution of phosgene (20% in toluene, 0.092 mL, 0.174 mmol) inDCM (2 mL) was treated slowly with a solution of Example B6 (26 mg,0.166 mmol) and pyridine (0.027 mL, 0.331 mmol) in DCM (2 mL), stirredat 0° C. for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (2 mL), treated with pyridine (0.0400 mL, 0.495 mmol),cooled to 0° C., treated slowly with a solution of Example A2 (36 mg,0.165 mmol) in DCM (2 mL), warmed to RT and stirred for 1.5 h. Themixture was diluted with water, extracted with DCM and the organic layerwas washed with water, then brine, dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford(S)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide(33 mg, 45%). 1H NMR (400 MHz, DMSO-d₆): δ 10.95 (s, 1H), 8.38 (d, J=5.8Hz, 1H), 8.27 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H),7.97 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.25 (s, 1H), 6.71 (d, J=5.5Hz, 1H), 4.57-4.49 (m, 1H), 3.91-3.86 (m, 1H), 3.84 (s, 3H), 3.83-3.76(m, 3H), 3.70-3.57 (m, 2H), 3.51-3.43 (m, 2H), 2.19-2.09 (m, 1H),2.02-1.91 (m, 1H); MS (ESI) m/z: 450.1 (M+H⁺).

Example 13

A 0° C. suspension of 2,2-dimethyltetrahydro-2H-pyran-4-amine (0.806 g,6.24 mmol) in THF (30 mL) was treated drop-wise with 2-chloroethylisocyanate (0.585 mL, 6.86 mmol), allowed to warm to RT as the coolingbath expired and stirred overnight. The mixture was treated withadditional 2-chloroethyl isocyanate (160 μL) and stirred at RT for anadditional 24 hours, then concentrated to dryness, the residue dissolvedin EtOAc and washed with saturated NH₄Cl (1×), NaHCO₃ (1×) and brine(1×), dried over MgSO₄ and concentrated to dryness to afford1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (700 mg,48%) as a yellow oil. MS (ESI) m/z: 235.1 (M+H⁺).

A −20° C. solution of1-(2-chloroethyl)-3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)urea (0.700 g,2.98 mmol) in THF (15 mL), under Ar, was treated with NaH (60% inmineral oil, 0.298 g, 7.46 mmol), allowed to warm to RT as the coolingbath expired and stirred overnight. The mixture was cooled to 0° C.,quenched with saturated NH₄Cl, warmed to RT, treated with brine,extracted with EtOAc (2×) and the combined organics were dried overMgSO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one as a whitesolid (155 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.24 (s, 1H), 3.85 (m,1H), 3.67-3.54 (m, 2H), 3.26-3.13 (m, 4H), 1.53-1.37 (m, 4H), 1.14 (d,J=10.2 Hz, 6H); MS (ESI) m/z: 199.2 (M+H⁺).

A 0° C. solution of phosgene (20% in toluene, 0.361 mL, 0.676 mmol) inDCM (2 mL), under Ar, was treated slowly drop-wise with a solution of1-(2,2-dimethyltetrahydro-2H-pyran-4-yl)imidazolidin-2-one (0.067 g,0.338 mmol) and pyridine (0.055 mL, 0.676 mmol) in DCM (1 mL). Themixture was warmed to RT and concentrated to dryness to afford3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonylchloride as a yellow solid which was carried on to the next stepassuming 100% yield (88 mg).

A 0° C. solution of Example A2 (0.060 g, 0.224 mmol) and TEA (0.094 mL,0.673 mmol) in DCM (1 mL) was treated with a solution of crude3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-2-oxoimidazolidine-1-carbonylchloride (0.088 g, 0.337 mmol) in DCM (1 mL). The mixture was warmed toRT, stirred for 0.5 h, then concentrated to dryness and purified viasilica gel chromatography (MeOH/DCM) to afford3-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamideas an off-white solid (74 mg, 67%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.96(s, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.21 (m, 1H), 8.05 (m,1H), 7.96 (d, J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d,J=2.4 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 4.04 (m, 1H), 3.84 (s, 3H),3.84-3.75 (m, 2H), 3.70-3.59 (m, 2H), 3.46-3.39 (m, 2H), 1.60-1.47 (m,4H), 1.18 (d, J=15.1 Hz, 6H); MS (ESI) m/z: 492.2 (M+H⁺).

Example 14

A solution of Example A3 (0.35 g, 1.260 mmol) in DMF (5 mL) was spargedwith argon, treated with TEA (1 mL) trimethylsilylacetylene (0.531 mL,3.78 mmol), copper(I) iodide (0.024 g, 0.126 mmol) andtrans-dichlorobis(triphenylphosphine)palladium(0) (0.088 g, 0.126 mmol)and heated at 75° C. under argon for 16 h. The mixture was cooled to RT,treated with EtOAc, solids removed via filtration through diatomaceousearth, rinsed well with EtOAc and H₂O and the layers of the filtrateseparated. The aqueous layer was extracted with EtOAc (1×) and thecombined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness. The resulting material was dissolved in MeOH(20 mL), treated with K₂CO₃ (300 mg) and stirred at RT for 1 h. Themixture was concentrated to dryness, treated with EtOAc, sonicated, thesolids removed via filtration through diatomaceous earth, rinsed wellwith EtOAc and the filtrate concentrated to dryness and purified viasilica gel chromatography (EtOAc/Hex) to affordN-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (102mg, 30%) as a light red solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.62 (s,1H); 8.40 (d, J=5.8 Hz, 1H); 8.01 (d, J=8.8 Hz, 1H); 7.60 (d, J=6.0 Hz,1H); 7.04 (d, J=2.5 Hz, 1H); 6.89 (dd, J=5.8, 2.6 Hz, 1H); 4.34 (s, 1H);2.22 (s, 3H); 2.07 (s, 3H); MS (ESI) m/z: 268.1 (M+H⁺).

A solution of N-chlorosuccinimide (0.153 g, 1.145 mmol) in DMF (1 mL)was treated with acetaldoxime (0.068 g, 1.145 mmol), stirred at RT for30 min, then added to a solution ofN-(5-((2-ethynylpyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (0.102g, 0.382 mmol) and TEA (0.5 mL) in DMF (1 mL) and heated at 60° C. for 1h. The mixture was cooled to RT, treated with H₂O, extracted with EtOAc(2×) and the combined organics were washed with H₂O, then brine, driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to affordN-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide(110 mg, 89%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.64 (s,1H), 8.55 (d, J=5.7 Hz, 1H), 8.03 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz,1H), 7.35 (d, J=2.5 Hz, 1H), 6.96 (m, 2H), 2.28 (s, 3H), 2.25 (s, 3H),2.08 (s, 3H); MS (ESI) m/z: 325.1 (M+H⁺).

A mixture ofN-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide(0.11 g, 0.339 mmol) and 2M HCl (1.696 mL, 3.39 mmol) in THF (3 mL) washeated at 60° C. for 4 h. The mixture was cooled to RT, treated withEtOAc and H₂O, neutralized with NaHCO₃, the layers separated and theaqueous layer extracted with EtOAc (1×). The combined organics werewashed with brine, dried over Na₂SO₄ and concentrated to dryness toafford6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine(90 mg, 94%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.51 (d,J=5.7 Hz, 1H); 7.26 (d, J=2.5 Hz, 1H); 7.22 (d, J=8.7 Hz, 1H); 6.95 (s,1H); 6.89 (dd, J=5.7, 2.5 Hz, 1H); 6.36 (d, J=8.7 Hz, 1H); 6.00 (s, 2H);2.28 (s, 3H); 2.06 (s, 3H); MS (ESI) m/z: 283.1 (M+H⁺).

Phosgene (20% in toluene, 0.613 g, 1.24 mmol) was treated with asolution of Example B1 (0.063 g, 0.37 mmol) and pyridine (0.1 mL, 1.24mmol) in DCM (2 mL), stirred for 15 min, then concentrated to dryness.The residue was dissolved in DCM (2 mL), treated with a solution of6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine(0.07 g, 0.25 mmol) and TEA (0.17 mL, 1.24 mmol) in DCM (2 mL) andstirred at RT for 1 h. The mixture was treated with satd. NaHCO₃,extracted with EtOAc (2×) and the combined organics were washed withbrine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/DCM) to affordN-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(75 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 8.55 (d, J=5.7Hz, 1H), 7.92 (d, J=8.8 Hz, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.34 (d, J=2.5Hz, 1H), 6.98 (s, 1H), 6.96 (dd, J=5.7, 2.5 Hz, 1H), 3.95-3.77 (m, 5H),3.48-3.35 (m, 4H), 2.28 (s, 3H), 2.24 (s, 3H), 1.71-1.70 (m, 2H), 1.60(d, J=12.5 Hz, 2H); MS (ESI) m/z: 479.2 (M+H⁺).

Example 15

A solution of Example B7 (0.085 g, 0.505 mmol) and pyridine (0.133 g,1.684 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.833g, 1.684 mmol), under Ar, stirred for 15 min, then concentrated todryness. The residue was dissolved in DCM (2 mL), treated with asolution of Example A2 (0.09 g, 0.337 mmol) and TEA (0.102 g, 1.010mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treatedwith water, extracted with DCM (2×) and the combined organics werewashed with brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to afford3-cyclohexyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(100 mg, 64%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.99 (s,1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d,J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.79 (m, 2H),3.61 (m, 1H), 3.43 (m, 2H), 1.67 (m, 5H), 1.35 (m, 4H), 1.08 (m, 1H); MS(ESI) m/z: 462.2 (M+H⁺).

Example 16

A solution of Example B8 (95 mg, 0.601 mmol) and pyridine (71 mg, 0.901mmol) in DCM (4 mL) was added phosgene (20% in toluene, 743 mg, 1.501mmol), under Ar, stirred for 15 minutes, then concentrated to dryness.The residue was treated with a solution of Example A2 (80 mg, 0.300mmol) and TEA (152 mg, 1.501 mmol) in DCM (4 mL) and stirred at RT for0.5 h. The mixture was treated with water, extracted with EtOAc (2×) andthe combined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to afford(S)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(79 mg, 58%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s,1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.22-8.21 (m, 1H), 8.06-8.05(m, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 4.11-4.08 (m, 1H), 3.84 (s,3H), 3.83-3.77 (m, 2H), 3.50-3.33 (m, 4H), 3.26 (s, 3H), 1.09 (d, J=6.9Hz, 3H); MS (ESI) m/z: 452.2 (M+H⁺).

Example 17

A 0° C. solution of phosgene (20% in toluene, 0.711 mL, 0.980 mmol) inDCM (6 mL) was treated slowly drop-wise with a solution of Example B9(0.129 g, 0.700 mmol) and pyridine (0.113 mL, 1.400 mmol) in DCM (2 mL),warmed to RT, stirred for 0.5 h, then concentrated to dryness. Theresidue was dissolved in DCM (2 mL), added to a 0° C. solution ofExample A2 (0.058 g, 0.218 mmol) and TEA (0.091 mL, 0.654 mmol) in DCM(1 mL), warmed to RT and stirred for 0.5 h. The mixture was treated withwater, stirred for 15 min and the layers separated. The organic layerwas washed with additional water (2×), dried over MgSO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford3-(2-(1-methoxycyclopropyl)ethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(25 mg, 24%) as a white solid. 1H NMR (400 MHz, DMSO-d₆): δ 10.99 (s,1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H),7.22 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.80(m, 2H), 3.50 (m, 2H), 3.34 (m, 2H), 3.17 (s, 3H), 1.77 (t, J=7.4 Hz,2H), 0.67 (m, 2H), 0.42 (m, 2H); MS (ESI) m/z: 478.2 (M+H⁺).

Example 18

A 0° C. solution of phosgene (15% in toluene, 30 mL, 42.5 mmol) in DCM(25 mL) was treated drop-wise with a solution of pyridine (5 mL) andExample B3 (3.07 g, 21.33 mmol) in DCM (25 mL), stirred at RT for 1 h,then concentrated to dryness. The residue was dissolved in DCM (25 mL),added to a 0° C. solution of Example A4 (3.0 g, 10.66 mmol) and pyridine(5 mL) in DCM (25 mL), warmed to RT and stirred overnight. The mixturewas treated with satd. NaHCO₃, stirred for 0.5 h, the layers separatedand the aqueous layer extracted with additional DCM (2×). The combinedorganics were washed with brine, dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM). Thematerial was treated with EtOAc, sonicated and the resulting solid wascollected via filtration to afford3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(3.05 g, 63%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.88 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=8.8Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.81-3.79 (m, 2H), 3.51-3.49 (m, 4H),3.41-3.37 (m, 2H), 3.26 (s, 3H), 2.24 (s, 3H); MS (ESI) m/z: 452.2(M+H⁺).

Example 19

A solution of Example B5 (0.081 g, 0.512 mmol) and pyridine (0.129 mL,1.600 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.791g, 1.60 mmol), under Ar, stirred for 15 minutes, then concentrated todryness. The residue was dissolved in DCM (2 mL), treated with asolution of Example A4 (0.09 g, 0.320 mmol) and TEA (0.134 mL, 0.960mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treatedwith water, extracted with DCM (2×) and the combined organics werewashed with brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to afford3-(3-methoxypropyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(86 mg, 58%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s,1H), 8.35 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.96 (s, 1H), 7.90 (d, J=8.8Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.61 (dd,J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.81-3.79 (m, 2H), 3.49-3.43 (m, 2H),3.37-3.33 (m, 2H), 3.29-3.24 (m, 2H), 3.23 (s, 3H), 2.24 (s, 3H),1.78-1.70 (m, 2H); MS (ESI) m/z: 466.2 (M+H⁺).

Example 20

A 0° C. solution of phosgene (20% in toluene, 0.853 mL, 1.177 mmol) inDCM (6 mL) was treated slowly drop-wise with a solution of Example B10(0.119 g, 0.841 mmol) and pyridine (0.136 mL, 1.681 mmol) in DCM (2 mL),warmed to RT, stirred for 0.5 h, then concentrated to dryness. Theresidue was dissolved in DCM (2 mL), added to a 0° C. solution ofExample A4 (0.074 g, 0.263 mmol) and TEA (0.110 mL, 0.788 mmol) in DCM(1 mL), warmed to RT and stirred overnight. The mixture was diluted withDCM, washed with water (3×), dried over MgSO₄, concentrated to drynessand purified via silica gel chromatography (MeOH/DCM) to affordN-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide(39 mg, 33%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.78 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.89(d, J=8.8 Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59(dd, J=5.7, 2.4 Hz, 1H), 5.02 (m, 1H), 4.77 (t, J=6.6 Hz, 2H), 4.69 (t,J=7.3 Hz, 2H), 3.84 (m, 5H), 3.73 (m, 2H), 2.24 (s, 3H); MS (ESI) m/z:450.2 (M+H⁺).

Example 21

A solution of Example B11 (0.1025 g, 0.393 mmol) in DCM (4 mL) wastreated with a solution of Example A2 (0.105 g, 0.393 mmol) and TEA(0.082 mL, 0.590 mmol) in DCM (4 mL), stirred at RT for 1 h, dilutedwith DCM, washed with water (2×), then brine (1×), dried over MgSO₄ andconcentrated to dryness. The material was purified via silica gelchromatography (MeOH/EtOAc) to affordN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide(93 mg, 48%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s,1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.73 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d,J=2.4 Hz, 1H), 6.70 (dd, J=5.7, 2.4 Hz, 1H), 4.25 (t, J=5.1 Hz, 2H),3.84-3.82 (m, 5H), 3.54-3.53 (m, 4H); MS (ESI) m/z: 492.1 (M+H⁺).

Example 22

A solution of Example B7 (0.086 g, 0.514 mmol) and pyridine (0.122 mL,1.511 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.747g, 1.511 mmol), under Ar, stirred for 15 min, then concentrated todryness. The residue was dissolved in DCM (2 mL), treated with asolution of Example A4 (0.085 g, 0.302 mmol) and TEA (0.126 mL, 0.906mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treatedwith water, extracted with DCM (2×) and the combined organics werewashed with brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to afford3-cyclohexyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(110 mg, 79%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.80-3.78 (m, 2H), 3.60-3.58 (m, 1H),3.50-3.52 (m, 2H), 2.24 (s, 3H), 1.70-1.66 (m, 5H), 1.39-1.38 (m, 4H),1.11-1.08 (m, 1H); MS (ESI) m/z: 476.2 (M+H⁺).

Example 23

A 0° C. solution of phosgene (20% in toluene, 0.445 mL, 0.845 mmol) inDCM (4 mL) was treated slowly with a solution of Example B6 (0.110 g,0.704 mmol) and pyridine (0.114 mL, 1.409 mmol) in DCM (4 mL), stirredat 0° C. 1 h, then concentrated to dryness. The residue was dissolved inDCM (4 mL), treated with a solution of Example A4 (0.149 g, 0.528 mmol)and TEA (0.147 mL, 1.056 mmol) in DCM (4 mL) and stirred at RT for 1.5h. The mixture was diluted with DCM, washed with water (2×), thecombined aqueous washes were back-extracted with DCM (1×) and thecombined organics were washed with brine (2×), dried over MgSO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to afford(S)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide(139 mg, 43%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.87 (s,1H), 8.35 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 4.51-4.50 (m, 1H), 3.91-3.86 (m, 1H), 3.84 (s, 3H),3.82-3.75 (m, 3H), 3.70-3.60 (m, 2H), 3.47 (t, J=8.2 Hz, 2H), 2.24 (s,3H), 2.20-2.10 (m, 1H), 2.01-1.91 (m, 1H); MS (ESI) m/z: 464.2 (M+H⁺).

Example 24

A 0° C. solution of triphosgene (0.500 g, 1.685 mmol) in MeCN (10 mL)was treated with a solution of imidazolidin-2-one (0.800 g, 9.29 mmol)in MeCN (10 mL), stirred at RT for 0.5 h, added to a suspension ofExample A2 (0.800 g, 2.99 mmol) in MeCN (10 mL) and stirred at RT for 4h. The solids were collected via filtration to affordN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(862 mg, 76%) as an off-white solid. MS (ESI) m/z: 380.1 (M+H⁺).

A 0° C. solution ofN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(0.350 g, 0.923 mmol) in DMF (5 mL) was treated with NaH (60% in mineraloil, 0.100 g, 2.50 mmol), stirred at RT for 0.5 h, treated with ExampleC4 (0.500 g, 1.836 mmol) and stirred at RT overnight. The mixture wastreated with water, extracted with EtOAc (3×) and the combined organicswere dried over Na₂SO₄, concentrated to dryness and purified via silicagel chromatography (MeOH/DCM) to afford3-(3-methoxy-3-methylbutyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(138 mg, 28%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s,1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J=2.9 Hz, 1H), 8.06(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.80 (m, 2H),3.47 (t, J=8.2 Hz, 2H), 3.25 (m, 2H), 3.09 (s, 3H), 1.71 (m, 2H), 1.11(s, 6H); MS (ESI) m/z: 480.2 (M+H⁺).

Example 25

A 0° C. solution of phosgene (20% in toluene, 2.00 mL, 3.78 mmol) wastreated with a solution of Example B12 (0.200 g, 0.979 mmol) andpyridine (0.150 g, 1.896 mmol) in DCM (10 mL), stirred at RT for 0.5 h,then concentrated to dryness. The residue was treated with a solution ofExample A2 (0.150 g, 0.561 mmol) and pyridine (0.150 g, 1.896 mmol) inDCM (10 mL) and stirred at RT for 1 h. The mixture was concentrated todryness and purified via silica gel chromatography (EtOAc/DCM) to afford3-(4,4-difluorocyclohexyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(90 mg, 32%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (s,1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (m, 6H), 3.45 (t,J=8.2 Hz, 2H), 2.13 (m, 4H), 1.73 (m, 4H); MS (ESI) m/z: 498.2 (M+H⁺).

Example 26

A 0° C. solution of phosgene (20% in toluene, 1.50 mL, 2.84 mmol) wastreated with a solution of Example B12 (0.200 g, 0.979 mmol) andpyridine (0.150 g, 1.896 mmol) in DCM (10 mL), stirred at RT for 0.5 h,then concentrated to dryness. The residue was treated with a solution ofExample A4 (0.150 g, 0.533 mmol) and pyridine (0.150 g, 1.896 mmol) inDCM (10 mL) and stirred at RT for 2 h. The mixture was concentrated todryness and purified via silica gel chromatography (EtOAc/DCM) to afford3-(4,4-difluorocyclohexyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(116 mg, 42%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.88 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 3.84 (m, 6H), 3.45 (t, J=8.2 Hz, 2H), 2.24 (s, 3H),2.06 (m, 4H), 1.76 (s, 4H); MS (ESI) m/z: 512.2 (M+H⁺).

Example 27

A solution of Example B13 (0.196 g, 0.896 mmol) in DCM (4 mL) wastreated with a solution of Example A2 (0.160 g, 0.598 mmol) and TEA(0.250 mL, 1.793 mmol) in DCM (4 mL) and stirred at RT for 1.5 h. Themixture was treated with water, extracted with DCM (2×) and the combinedorganics were washed with brine (2×), dried over MgSO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford(R)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide(150 mg, 56%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s,1H), 8.37 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d,J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 4.54-4.52 (m, 1H),3.88-3.87 (m, 1H), 3.84 (s, 3H), 3.80-3.78 (m, 3H), 3.64-3.63 (m, 2H),3.47 (t, J=8.2 Hz, 2H), 2.15-2.14 (m, 1H), 1.97-1.94 (m, 1H); MS (ESI)m/z: 450.1 (M+H⁺).

Example 28

A solution of Example B13 (0.196 g, 0.896 mmol) in DCM (4 mL) wastreated with a solution of Example A4 (0.168 g, 0.598 mmol) and TEA(0.249 mL, 1.793 mmol) in DCM (4 mL) and stirred at RT for 1.5 h. Themixture was treated with water, extracted with DCM (2×) and the combinedorganics were washed with brine (2×), dried over MgSO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford(R)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide(208 mg, 75%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.87 (s,1H), 8.35 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.61 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 4.54-4.48 (m, 1H), 3.88-3.87 (m, 1H), 3.84 (s, 3H),3.80-3.78 (m, 3H), 3.66-3.65 (m, 2H), 3.47 (t, J=8.2 Hz, 2H), 2.24 (s,3H), 2.15-2.13 (m, 1H), 1.98-1.95 (m, 1H); MS (ESI) m/z: 464.2 (M+H⁺).

Example 29

A 0° C. solution of Example B14 (0.159 g, 1.031 mmol) and pyridine(0.272 mL, 3.37 mmol) in DCM (5 mL) was treated drop-wise with phosgene(20% in toluene, 1.579 mL, 2.99 mmol), warmed to RT, added to a solutionof Example A4 (0.158 g, 0.561 mmol) and pyridine (0.136 mL, 1.684 mmol)in DCM (5 mL) and stirred at RT for 2 h. The mixture was treated withsatd. NaHCO₃, extracted with DCM (3×) and the combined organics weredried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford3-cyclopentyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(181 mg, 70%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.5 Hz, 1H), 4.22-4.13 (m, 1H), 3.84 (s, 3H), 3.79 (m, 2H), 3.44(m, 2H), 2.24 (s, 3H), 1.81-1.72 (m, 2H), 1.69-1.51 (m, 6H); MS (ESI)m/z: 462.2 (M+H⁺).

Example 30

A 0° C. solution of Example B14 (0.159 g, 1.031 mmol) and pyridine(0.272 mL, 3.37 mmol) in DCM (5 mL) was treated drop-wise with phosgene(20% in toluene, 1.579 mL, 2.99 mmol), warmed to RT, added to a solutionof Example A2 (0.15 g, 0.561 mmol) and pyridine (0.136 mL, 1.684 mmol)in DCM (5 mL) and stirred at RT for 2 h. The mixture was treated withsatd. NaHCO₃, extracted with DCM (3×) and the combined organics weredried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to afford3-cyclopentyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(72 mg, 29%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.00 (s,1H), 8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.22 (d, J=2.9 Hz, 1H), 8.07(d, J=9.0 Hz, 1H), 7.96 (s, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d,J=2.4 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 4.20 (m, 1H), 3.84 (s, 3H),3.80-3.79 (m, 2H), 3.45-3.44 (m, 2H), 1.80-1.72 (m, 2H), 1.69-1.51 (m,6H); MS (ESI) m/z: 448.2 (M+H⁺).

Example 31

A 0° C. solution of Example A2 (0.114 g, 0.425 mmol) and TEA (0.1 mL) inDCM (5 mL) was treated with a solution of Example B15 (0.22 g, 0.850mmol) in DCM (5 mL), stirred at 0° C. for 0.5 h, then warmed to RT andstirred overnight. The mixture was treated with water, extracted withEtOAc and the organic layer was washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to afford3-cyclohexyl-4,4-dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(22 mg, 9.5%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.67 (s, 1H), 8.35 (d,J=5.7 Hz, 1H), 8.23 (m, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.94 (s, 1H), 7.69(dd, J=9.0, 2.9 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 6.68 (dd, J=5.7, 2.4Hz, 1H), 3.83 (s, 3H), 3.73 (s, 2H), 3.40 (s, 1H), 1.70 (m, 4H), 1.43(s, 6H), 1.25 (m, 6H); MS (ESI) m/z: 490.2 (M+H⁺).

Example 32

A 0° C. solution of Example A4 (0.024 g, 0.085 mmol) and TEA (0.1 mL) inDCM (5 mL) was treated with a solution of Example B15 (0.044 g, 0.171mmol) in DCM (5 mL), stirred at 0° C. for 0.5 h, then warmed to RT andstirred overnight. The mixture was treated with water, extracted withEtOAc and the organic layer was washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/Hex) to afford3-cyclohexyl-4,4-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(16 mg, 33%). ¹H NMR (400 MHz, DMSO-d₆): δ 12.68 (s, 1H), 8.33 (d, J=5.7Hz, 1H), 8.23 (s, 1H), 7.94 (s, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.58 (d,J=8.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.5 Hz, 1H),3.83 (s, 3H), 3.73 (s, 2H), 3.47 (m, 1H), 2.22 (s, 3H), 1.72 (m, 4H),1.42 (s, 6H), 1.31 (s, 6H); MS (ESI) m/z: 504.2 (M+H⁺).

Example 33

A solution of triphosgene (0.200 g, 0.674 mmol) in DCM (5 mL) wastreated with a solution of Example B16 (0.500 g, 3.52 mmol) and pyridine(0.100 g, 1.264 mmol) in DCM (5 mL), stirred at RT for 0.5 h, thenconcentrated to dryness. The residue was treated with a solution ofExample A4 (0.150 g, 0.533 mmol) and pyridine (0.100 g, 1.264 mmol) inDCM (5 mL) and stirred at RT for 2 h. The mixture was concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford3-(tert-butyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(55 mg, 22%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.97(s, 1H), 8.34 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.88 (d,J=8.8 Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.58 (dd,J=5.7, 2.4 Hz, 1H), 3.83 (s, 3H), 3.70 (t, J=8.2 Hz, 2H), 3.50 (t, J=8.2Hz, 2H), 2.23 (s, 3H), 1.35 (s, 9H); MS (ESI) m/z: 450.2 (M+H⁺).

Example 34

A solution of triphosgene (0.200 g, 0.674 mmol) in DCM (5 mL) wastreated with a solution of Example B16 (0.500 g, 3.52 mmol) and pyridine(0.100 g, 1.264 mmol) in DCM (5 mL), stirred at RT for 0.5 h, thenconcentrated to dryness. The residue was treated with a solution ofExample A2 (0.150 g, 0.561 mmol) and pyridine (0.100 g, 1.264 mmol) inDCM (5 mL) and stirred at RT for 2 h. The mixture was concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford3-(tert-butyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(112 mg, 45%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 11.04(s, 1H), 8.35 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 8.20 (d, J=2.9 Hz, 1H),8.05 (d, J=9.0 Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J=9.0, 2.9 Hz, 1H), 7.21(d, J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.83 (s, 3H), 3.70 (t,J=8.2 Hz, 2H), 3.50 (t, J=8.2 Hz, 2H), 1.35 (s, 9H); MS (ESI) m/z: 436.2(M+H⁺).

Example 35

A solution of triphosgene (0.200 g, 0.674 mmol) in DCM (5 mL) wastreated with a solution of Example B17 (0.250 g, 1.950 mmol) andpyridine (0.100 g, 1.264 mmol) in DCM (5 mL), stirred at RT for 0.5 h,then concentrated to dryness. The residue was treated with a solution ofExample A4 (0.150 g, 0.533 mmol) and pyridine (0.100 g, 1.264 mmol) inDCM (5 mL) and stirred at RT for 2 h. The mixture was concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford3-isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(178 mg, 77%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s,1H), 8.33 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 7.94 (s, 1H), 7.88 (d, J=8.8Hz, 1H), 7.59 (d, J=8.8 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 6.57 (dd,J=5.7, 2.4 Hz, 1H), 4.00 (m, 1H), 3.83 (s, 3H), 3.78 (m, 2H), 3.40 (t,J=8.2 Hz, 2H), 2.22 (s, 3H), 1.12 (d, J=6.8 Hz, 6H); MS (ESI) m/z: 436.2(M+H⁺).

Example 36

A solution of triphosgene (0.200 g, 0.674 mmol) in DCM (5 mL) wastreated with a solution of Example B17 (0.250 g, 1.950 mmol) andpyridine (0.100 g, 1.264 mmol) in DCM (5 mL), stirred at RT for 0.5 h,then concentrated to dryness. The residue was treated with a solution ofExample A2 (0.150 g, 0.561 mmol) and pyridine (0.100 g, 1.264 mmol) inDCM (5 mL) and stirred at RT for 2 h. The mixture was concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(180 mg, 76%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s,1H), 8.35 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 8.21 (d, J=2.9 Hz, 1H), 8.05(d, J=9.0 Hz, 1H), 7.94 (s, 1H), 7.70 (dd, J=9.0, 2.9 Hz, 1H), 7.21 (d,J=2.4 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 4.02 (m, 1H), 3.83 (s, 3H),3.79 (m, 2H), 3.43 (t, J=8.2 Hz, 2H), 1.12 (d, J=6.8 Hz, 6H); MS (ESI)m/z: 422.2 (M+H⁺).

Example 37

A suspension of Example A6 (0.744 g, 2.80 mmol), Example C2 (0.65 g,3.08 mmol), and Cs₂CO₃ (2.74 g, 8.40 mmol) in DMF (7.5 mL) was spargedwith Ar, treated with Pd(PPh₃)₄ (0.323 g, 0.280 mmol) sparged again withAr and heated at 90° C. overnight. The mixture was cooled to RT, treatedwith EtOAc and the solids removed via filtration through diatomaceousearth. The filtrate was concentrated to dryness and purified via silicagel chromatography (MeOH/DCM) to afford2-methyl-6-nitro-3-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine(880 mg, 100%) as a brown solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.45 (d,J=5.6 Hz, 1H), 8.26 (d, J=0.7 Hz, 1H), 8.22 (d, J=8.7 Hz, 1H), 7.98 (d,J=0.7 Hz, 1H), 7.82 (d, J=8.7 Hz, 1H), 7.35 (d, J=2.4 Hz, 1H), 6.88 (dd,J=5.6, 2.4 Hz, 1H), 2.49 (s, 3H); MS (ESI) m/z: 315.1 (M+H⁺).

A solution of2-methyl-6-nitro-3-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine(1.6 g, 5.09 mmol) in MeOH (20 mL) and THF (20 mL) was treated withNH₄Cl (4.27 g, 80 mmol), then portion-wise with zinc powder (2.134 g,32.6 mmol) and stirred at RT for 0.5 h. The mixture was diluted withEtOAc, the solids removed via filtration through diatomaceous earth andthe filtrate concentrated to dryness. The residue was dissolved in hotEtOAc, cooled to RT and the resulting solid collected via filtration toafford6-methyl-5-((2-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(1.25 g, 86%) as a pink solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.77 (dd,J=5.7, 0.5 Hz, 1H), 8.54 (d, J=0.7 Hz, 1H), 8.36 (d, J=0.7 Hz, 1H), 7.62(d, J=8.6 Hz, 1H), 7.51-7.50 (m, 1H), 6.98 (dd, J=5.7, 2.4 Hz, 1H), 6.92(dd, J=8.6, 0.7 Hz, 1H), 5.84 (s, 2H), 2.57 (s, 3H); MS (ESI) m/z: 285.1(M+H⁺).

A solution of Example B13 (0.208 g, 0.950 mmol) in DCM (4 mL) wastreated with a solution of6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(0.15 g, 0.528 mmol) and TEA (0.219 mL, 1.583 mmol) in DCM (4 mL) andstirred at RT for 1.5 h. The mixture was treated with brine, extractedwith EtOAc (3×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(EtOAc/DCM). The material was treated with MeCN and Et₂O, sonicated andthe resulting solid collected via filtration to afford(R)—N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide(120 mg, 49%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.87 (s, 1H), 8.34 (d,J=5.7 Hz, 1H), 8.24 (d, J=0.7 Hz, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.89 (d,J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 4.45 (m, 1H), 3.87 (d, J=6.3 Hz, 1H), 3.79 (m, 3H),3.65 (m, 2H), 3.47 (m, 2H), 2.24 (s, 3H), 2.14 (m, 1H), 1.96 (m, 1H); MS(ESI) m/z: 467.2 (M+H⁺).

Example 38

A solution of Example B8 (180 mg, 1.138 mmol) and pyridine (225 mg, 2.84mmol) in DCM (6 mL) was added to phosgene (15% in toluene, 1.876 mg,2.84 mmol) under Ar, stirred for 15 min, then concentrated to dryness.The residue was dissolved in DCM (2 mL), treated with a solution ofExample A4 (160 mg, 0.569 mmol) and TEA (288 mg, 2.84 mmol) in DCM (4mL) and stirred at RT for 2 h. The mixture was treated with water,extracted with EtOAc (2×) and the combined organics were washed withbrine, dried over Na₂SO₄, concentrated to dryness and purified viareverse-phase chromatography (MeCN/H₂O with 0.1% TFA). The organics wereremoved under reduced pressure, the aqueous residue neutralized withsatd. NaHCO₃ and extracted with EtOAc (2×). The combined organics weredried over Na₂SO₄, concentrated to dryness and re-purified via silicagel chromatography (MeOH/DCM) to afford(S)-3-(1-methoxypropan-2-yl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(49 mg, 18%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 8.34 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60 (d,J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H),4.10-4.07 (m, 1H), 3.84 (s, 3H), 3.80 (m, 2H), 3.48-3.32 (m, 4H), 3.26(s, 3H), 2.24 (s, 3H), 1.09 (d, J=6.9 Hz, 3H); MS (ESI) m/z: 466.2(M+H⁺).

Example 39

A mixture of Example C5 (0.200 g, 0.493 mmol), Example C2 (0.114 g,0.542 mmol) and K₂CO₃ (0.272 g, 1.971 mmol) in dioxane (8 mL) and water(2 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (0.085 g, 0.074mmol), sparged again with Ar and heated at 90° C. overnight. The mixturewas cooled to RT, treated with satd. NaHCO₃, extracted with EtOAc (3×)and the combined organics were dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(130 mg, 58%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.88 (s,1H), 8.34 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=8.8Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd,J=5.7, 2.4 Hz, 1H), 3.80 (m, 2H), 3.54-3.46 (m, 4H), 3.38 (m, 2H), 3.26(s, 3H), 2.24 (s, 3H); MS (ESI) m/z: 455.2 (M+H⁺).

Example 40

A biphasic mixture of 4-aminotetrahydropyran hydrochloride (1.0 g, 7.27mmol) in EtOAc (20 mL) and satd. NaHCO₃ (20 mL) was treated withisopropenyl chloroformate (0.874 mL, 7.99 mmol), stirred at RT for 2 hand the layers separated. The aqueous layer was extracted with EtOAc(1×) and the combined organics were washed with brine, dried over Na₂SO₄and concentrated to dryness to afford prop-1-en-2-yl(tetrahydro-2H-pyran-4-yl)carbamate (1.2 g, 89%). ¹H NMR (400 MHz,DMSO-d₆): δ 7.48 (d, J=7.7 Hz, 1H), 4.57 (d, J=7.9 Hz, 2H), 3.80-3.78(m, 2H), 3.51-3.40 (m, 1H), 3.33-3.25 (m, 2H), 1.83 (s, 3H), 1.69 (m,2H), 1.43-1.32 (m, 2H).

A solution of prop-1-en-2-yl (tetrahydro-2H-pyran-4-yl)carbamate (0.50g, 2.70 mmol) in dioxane (20 mL) was treated with DBU (0.1 mL) andpropargylamine (0.149 g, 2.70 mmol) and heated at 90° C. overnight. Themixture was cooled to RT, treated with brine and extracted with EtOAc(3×). The combined organics were dried over Na₂SO₄, concentrated todryness, treated with Et₂O and the resulting solid collected viafiltration to afford 1-(prop-2-yn-1-yl)-3-(tetrahydro-2H-pyran-4-yl)urea(400 mg, 81%). ¹H NMR (400 MHz, DMSO-d₆): δ 6.00 (m, 1H), 5.99 (m, 1H),3.76 (m, 2H), 3.75 (m, 2H), 3.56 (m, 1H), 3.30 (m, 2H), 3.02 (t, J=2.5Hz, 1H), 1.68 (m, 2H), 1.29 (m, 2H); MS (ESI) m/z: 183.1 (M+H⁺).

A 5° C. solution of 1-(prop-2-yn-1-yl)-3-(tetrahydro-2H-pyran-4-yl)urea(0.40 g, 2.195 mmol) in THF (20 mL) under Ar, was treated with NaH (60%in mineral oil, 0.097 g, 2.415 mmol), warmed to RT and stirredovernight. The mixture was treated with satd. NH₄Cl, extracted withEtOAc (2×) and the combined organics were washed with 5% LiCl, thenbrine and dried over Na₂SO₄. The solution was treated with Pd on C (260mg) and hydrogenated (30 psi) for 5 h. The mixture was filtered, treatedwith fresh Pd on C (260 mg) and hydrogenated (44 psi) overnight. Thesolids were removed via filtration through diatomaceous earth, washedwith EtOAc and the filtrate concentrated to dryness to afford crude5-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one (190 mg, 47%)which was used without further purification. MS (ESI) m/z: 185.1 (M+H⁺).

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and 5-methyl-1-(tetrahydro-2H-pyran-4-yl)imidazolidin-2-one (0.103g, 0.561 mmol) in DCM (5 mL), stirred at RT for 1 h, then concentratedto dryness. The residue was dissolved in DCM (5 mL), cooled to 0° C.,treated with a solution of Example A2 (0.10 g, 0.374 mmol) and pyridine(0.1 mL) in DCM (5 mL), warmed to RT and stirred overnight. The solidswere removed via filtration, washed with DCM and the filtrateconcentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to afford4-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(16 mg, 9%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 8.36 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.06 (d, J=9.0 Hz, 1H),7.95 (s, 1H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H), 6.68(dd, J=5.7, 2.4 Hz, 1H), 3.90 (m, 4H), 3.87 (m, 1H), 3.84 (s, 3H), 3.66(m, 1H), 3.39 (m, 1H), 3.34 (m, 1H), 2.05 (m, 1H), 1.90 (m, 1H), 1.70(m, 1H), 1.68 (m, 1H), 1.28 (d, J=5.4 Hz, 3H); MS (ESI) m/z: 478.2(M+H⁺).

Example 41

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and 1-methylimidazolidin-2-one (0.053 g, 0.533 mmol) in DCM (5mL), stirred at RT for 1 h, then concentrated to dryness. The residuewas dissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A4 (0.10 g, 0.355 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred overnight. The solids were removed viafiltration, washed with DCM and the filtrate concentrated to dryness.The residue was treated with EtOAc, the solid collected via filtrationand purified via reverse-phase chromatography (MeCN/H₂O with 0.1% TFA).The combined fractions were treated with satd. NaHCO₃, extracted withEtOAc and the organic layer dried over Na₂SO₄ and concentrated todryness to afford3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(66 mg, 46%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s, 1H), 8.34 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.60 (d,J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H),3.84 (s, 3H), 3.79 (m, 2H), 3.44 (m, 2H), 2.80 (s, 3H), 2.24 (s, 3H); MS(ESI) m/z: 408.2 (M+H⁺).

Example 42

A 0° C. solution of phosgene (15% in toluene, 18.3 mL, 25.6 mmol) in DCM(30 mL) was treated drop-wise with a solution of pyridine (2.1 mL, 26.1mmol) and Example B18 (2.0 g, 17.5 mmol) in DCM (5 mL), stirred at RTovernight, then concentrated to dryness. The residue was dissolved inDCM (10 mL) and the resultant mixture was added to a stirring solutionof Example A4 (4.8 g, 17.1 mmol) and pyridine (2.1 mL, 26.1 mmol) in THF(50 mL). The reaction mixture was stirred overnight at RT. The mixturewas concentrated to dryness and the residue was partitioned with EtOAcand with satd. NaHCO₃. The aqueous portion was extracted with EtOAc (3×)and the combined organics were dried over Na₂SO₄ and concentrated invacuo. The residue was twice purified by silica gel chromatography (6%MeOH/DCM) to afford a yellow oil. The oil was treated with Et₂O and themixture was sonicated for ˜30 min. The resulting white solid wascollected by filtration, washed with Et₂O and dried under vacuum toprovide3-ethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(4.00 g, 55%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.34 (d,J=5.7 Hz, 1H), 8.25 (s, 1 H), 7.95 (d, J=0.7 Hz, 1H), 7.90 (d, J=8.8 Hz,1H), 7.60 (d, J=8.8 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7,2.4 Hz, 1H), 3.84 (s, 3H), 3.80 (m, 2H), 3.46 (m, 2H), 3.25 (q, J=7.2Hz, 2H), 2.24 (s, 3H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 422.2(M+H⁺).

Example 43

A 0° C. solution of phosgene (15% in toluene, 2.5 mL, 3.54 mmol) in DCM(5 mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B19 (0.090 g, 0.533 mmol) in DCM (5 mL), stirred at RTfor 1 h, then concentrated to dryness. The residue was dissolved in DCM(5 mL), cooled to 0° C., treated with a solution of Example A4 (0.10 g,0.355 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred for 4 h. The solids were removed via filtration, washed with DCMand the filtrate concentrated to dryness. The residue was treated withEtOAc, the solid collected via filtration and purified via reverse-phasechromatography (MeCN/H₂O with 0.1% TFA). The combined fractions weretreated with satd. NaHCO₃, extracted with EtOAc and the organic layerdried over Na₂SO₄ and concentrated to dryness to affordN-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(75 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 8.35 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 7.95 (d, J=0.7 Hz, 1H), 7.90 (d, J=8.8 Hz, 1H),7.63 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz,1H), 4.11 (q, J=9.6 Hz, 2H), 3.90 (m, 2H), 3.84 (s, 3H), 3.59 (m, 2H),2.25 (s, 3H); MS (ESI) m/z: 476.1 (M+H⁺).

Example 44

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and 1-methylimidazolidin-2-one (0.056 g, 0.561 mmol) in DCM (5mL), stirred at RT for 2 h, then concentrated to dryness. The residuewas dissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A2 (0.10 g, 0.374 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred for 4 h. The solids were removed viafiltration, washed with DCM and the filtrate concentrated to dryness.The residue was treated with EtOAc/DCM/MeCN, allowed to stand overnightand the resulting solid collected via filtration to afford3-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(80 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.04 (s, 1H), 8.66 (s, 1H),8.52 (d, J=6.7 Hz, 1H), 8.35 (s, 1H), 8.32 (m, 1H), 8.12 (d, J=9.1 Hz,1H), 7.83 (dd, J=9.1, 2.9 Hz, 1H), 7.64 (s, 1H), 7.13 (m, 1H), 3.90 (s,3H), 3.80 (m, 2H), 3.45 (m, 2H), 2.80 (s, 3H); MS (ESI) m/z: 394.2(M+H⁺).

Example 45

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B18 (0.085 g, 0.748 mmol) in DCM (5 mL), stirred at RTfor 2 h, then concentrated to dryness. The residue was dissolved in DCM(5 mL), cooled to 0° C., treated with a solution of Example A2 (0.10 g,0.374 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred for 4 h. The solids were removed via filtration, washed with DCMand the filtrate concentrated to dryness. The residue was treated withEtOAc/DCM/MeCN, allowed to stand for 3 days and the resulting solidcollected via filtration to afford3-ethyl-N-(5-((2-(1-methyl-1-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(65 mg, 42%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.05 (s, 1H), 8.62 (s, 1H),8.52 (d, J=6.6 Hz, 1H), 8.32 (m, 1H), 8.30 (s, 1H), 8.12 (d, J=9.1 Hz,1H), 7.82 (dd, J=9.1, 2.9 Hz, 1H), 7.62 (s, 1H), 7.11 (s, 1H), 3.90 (s,3H), 3.81 (m, 2H), 3.46 (m, 2H), 3.26 (q, J=7.2 Hz, 2H), 1.09 (t, J=7.2Hz, 3H); MS (ESI) m/z: 408.2 (M+H⁺).

Example 46

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B20 (0.071 g, 0.748 mmol) in DCM (5 mL), stirred at RTfor 1 h, then concentrated to dryness. The residue was dissolved in DCM(5 mL), cooled to 0° C., treated with a solution of Example A2 (0.10 g,0.374 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred overnight. The mixture was treated with brine, extracted withEtOAc and the organic layer was dried over Na₂SO₄, concentrated todryness and purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA). The combined fractions were treated with satd. NaHCO₃,extracted with EtOAc and the organic layer was dried over Na₂SO₄ andconcentrated to dryness to afford3-cyclopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(107 mg, 67%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 8.37 (d,J=5.7 Hz, 1H), 8.26 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.07 (d, J=9.0 Hz,1H), 7.96 (s, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H),6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.85 (s, 3H), 3.75 (m, 2H), 3.41 (m, 2H),2.60 (s, 1H), 0.70 (d, J=5.4 Hz, 4H); MS (ESI) m/z: 420.2 (M+H⁺).

Example 47

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B20 (0.067 g, 0.533 mmol) in DCM (5 mL), stirred at RTfor 1 h, then concentrated to dryness. The residue was dissolved in DCM(5 mL), cooled to 0° C., treated with a solution of Example A4 (0.10 g,0.355 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred overnight. The mixture was treated with brine, extracted withEtOAc and the organic layer was dried over Na₂SO₄, concentrated todryness and purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA). The combined fractions were treated with satd. NaHCO₃,extracted with EtOAc and the organic layer was dried over Na₂SO₄ andconcentrated to dryness to afford3-cyclopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(72 mg, 46%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.35 (d, J=5.7Hz, 1H), 8.26 (s, 1H), 7.96 (d, J=0.7 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),7.61 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz,1H), 3.84 (s, 3H), 3.75 (m, 2H), 3.42 (m, 2H), 2.59 (m, 1H), 2.25 (s,3H), 0.71 (d, J=5.4 Hz, 4H); MS (ESI) m/z: 434.2 (M+H⁺).

Example 48

A 0° C. solution of phosgene (15% in toluene, 2.5 mL, 3.54 mmol) in DCM(5 mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B19 (0.094 g, 0.561 mmol) in DCM (5 mL), stirred at RTfor 1 h, then concentrated to dryness. The residue was dissolved in DCM(5 mL), cooled to 0° C., treated with a solution of Example A2 (0.10 g,0.374 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred overnight. The mixture was concentrated to dryness, treated withEt₂O/DCM and sonicated. The resulting solid was collected via filtrationto affordN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(95 mg, 55%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.38 (d, J=5.7Hz, 1H), 8.27 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H),7.97 (s, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.24 (d, J=2.4 Hz, 1H), 6.71(dd, J=5.7, 2.4 Hz, 1H), 4.12 (q, J=9.6 Hz, 2H), 3.88 (m, 2H), 3.85 (s,3H), 3.60 (m, 2H); MS (ESI) m/z: 462.2 (M+H⁺).

Example 49

A solution of phosgene (15% in toluene, 1.440 g, 2.184 mmol) under Ar,was treated with a solution of Example B1 (0.149 g, 0.874 mmol) andpyridine (0.104 g, 1.310 mmol) in DCM (4 mL), stirred for 15 min, thenconcentrated to dryness. The residue was treated with a solution ofExample A9 (0.129 g, 0.437 mmol) and TEA (0.221 g, 2.184 mmol) in DCM (4mL), stirred for 0.5 h, then treated with water and EtOAc. The layerswere separated, the aqueous layer extracted with additional EtOAc (1×)and the combined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via reverse-phase chromatography(MeCN/H₂O with 0.1% TFA). The organics were removed under reducedpressure and the aqueous residue was neutralized with satd. NaHCO₃ andextracted with EtOAc (2×). The combined organics were washed with brine,dried over Na₂SO₄ and concentrated to dryness to affordN-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(130 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 8.33 (d,J=5.7 Hz, 1H), 8.24 (s, 1H), 7.94 (d, J=0.7 Hz, 1H), 7.89 (d, J=8.8 Hz,1H), 7.59 (d, J=8.8 Hz, 1H), 7.17 (d, J=2.4 Hz, 1H), 6.58 (dd, J=5.7,2.4 Hz, 1H), 3.90-3.87 (m, 3H), 3.83 (s, 3H), 3.81-3.79 (m, 2H), 3.45(t, J=8.3 Hz, 2H), 3.37 (dd, J=12.4, 10.5 Hz, 2H), 2.56 (q, J=7.5 Hz,2H), 1.71 (qd, J=12.2, 4.5 Hz, 2H), 1.62-1.58 (m, 2H), 1.10 (t, J=7.5Hz, 3H); MS (ESI) m/z: 492.3 (M+H⁺).

Example 50

A 0° C. solution of phosgene (15% in toluene, 1.0 mL, 1.401 mmol) in DCM(15 mL) was treated drop-wise with a solution of Example B10 (0.1215 g,0.855 mmol) and pyridine (0.138 mL, 1.709 mmol) in DCM (2 mL), stirredat 0° C. for 0.5 h then concentrated to dryness. The residue wasdissolved in DCM (2 mL), added to a 0° C. solution of Example A2 (0.200g, 0.748 mmol) and pyridine (0.1 mL, 1.239 mmol) in DCM (5 mL), stirredat 0° C. for 0.5 h, then warmed to RT for 12 h. The mixture was treatedwith satd. NaHCO₃, the layers separated and the aqueous layer extractedwith DCM (3×). The combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM). The material was dissolved in toluene, concentrated todryness, dissolved in MeOH and concentrated to dryness to affordN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide(94 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.81 (s, 1H), 8.32 (d, J=5.7Hz, 1H), 8.21 (s, 1H), 8.18 (d, J=2.9 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H),7.91 (s, 1H), 7.67 (dd, J=9.0, 2.9 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.65(dd, J=5.7, 2.5 Hz, 1H), 5.03-4.95 (m, 1H), 4.72 (t, J=6.6 Hz, 2H), 4.64(t, J=7.4 Hz, 2H), 3.84-3.78 (m, 5H), 3.74-3.67 (m, 2H); MS (ESI) m/z:436.2 (M+H⁺).

Example 51

A mixture of Example C1 (0.250 g, 0.598 mmol), K₂CO₃ (0.165 g, 1.197mmol) and2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.157g, 0.718 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar,treated with Pd(PPh₃)₄ (0.069 g, 0.060 mmol), sparged again with Ar andheated at 95° C. for 36 h. The mixture was cooled to RT, treated withsatd. NaHCO₃ and extracted with EtOAc (4×). The combined organics weredried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to affordN-(5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(56 mg, 20%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s, 1H), 8.59 (d, J=5.6Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 8.27 (d, J=3.0 Hz, 1H), 8.08 (d, J=9.1Hz, 1H), 7.89 (s, 1H), 7.81-7.74 (m, 2H), 7.70 (d, J=2.4 Hz, 1H), 6.97(dd, J=5.6, 2.4 Hz, 1H), 3.93-3.78 (m, 5H), 3.49-3.35 (m, 4H), 2.52 (s,3H), 1.77-1.65 (m, 2H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 475.2 (M+H⁺).

Example 52

A mixture of Example C1 (0.200 g, 0.479 mmol), K₂CO₃ (0.132 g, 0.957mmol) and2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.126g, 0.574 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar,treated with Pd(PPh₃)₄ (0.055 g, 0.048 mmol), sparged again with Ar andheated at 95° C. overnight. The mixture was cooled to RT, treated withsatd. NaHCO₃ and extracted with EtOAc (4×). The combined organics weredried over Na₂SO₄, concentrated to dryness, suspended in MeCN andsonicated. The resulting solid was collected via filtration and dried toaffordN-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(118 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.97 (s, 1H), 9.09 (d,J=2.3 Hz, 1H), 8.54 (d, J=5.7 Hz, 1H), 8.29-8.24 (m, 2H), 8.07 (d, J=9.0Hz, 1H), 7.75 (dd, J=9.0, 2.9 Hz, 1H), 7.63 (d, J=2.4 Hz, 1H), 7.33 (d,J=8.2 Hz, 1H), 6.87 (dd, J=5.7, 2.4 Hz, 1H), 3.92-3.77 (m, 5H),3.48-3.34 (m, 4H), 2.50 (s, 3H), 1.77-1.65 (m, 2H), 1.62-1.55 (m, 2H);MS (ESI) m/z: 475.2 (M+H⁺).

Example 53

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B19 (0.086 g, 0.513 mmol) in DCM (5 mL), stirred at RTfor 1 h, then concentrated to dryness. The residue was dissolved in DCM(5 mL), cooled to 0° C., treated with a solution of Example A10 (0.1 g,0.342 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred overnight. The mixture was concentrated to dryness and purifiedvia reverse-phase chromatography (MeCN/H₂O with 0.1% TFA). The combinedfractions were treated with satd. NaHCO₃, extracted with EtOAc (3×) andthe combined organics were dried over Na₂SO₄ and concentrated todryness. The material was treated with MeCN and the solid collected viafiltration to affordN-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(53 mg, 31%). ¹H NMR (400 MHz, Acetone-d₆): 10.80 (s, 1H), 9.13 (d,J=2.4 Hz, 1H), 8.55 (d, J=5.6 Hz, 1H), 8.28 (dd, J=8.1, 2.4 Hz, 1H),8.04 (d, J=8.8 Hz, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.49 (d, J=2.4 Hz, 1H),7.31 (d, J=8.1 Hz, 1H), 6.82 (dd, J=5.6, 2.4 Hz, 1H), 4.12 (q, J=9.4 Hz,2H), 4.02 (m, 2H), 3.78 (m, 2H), 2.53 (s, 3H), 2.31 (s, 3H); MS (ESI)m/z: 487.2 (M+H⁺).

Example 54

A 0° C. solution of Example B1 (0.18 g, 1.058 mmol) and pyridine (0.25mL, 3.09 mmol) in DCM (5 mL) was treated drop-wise with phosgene (20% intoluene, 1.3 mL, 2.458 mmol), warmed to RT as the cooling bath expired,treated slowly with a solution of Example A10 (0.15 g, 0.513 mmol) andpyridine (0.15 mL, 1.855 mmol) in DCM (5 mL) and stirred at RTovernight. The mixture was treated with satd. NaHCO₃, the layersseparated and the aqueous layer extracted with EtOAc (4×). The combinedorganics were dried over Na₂SO₄, concentrated to dryness and treatedwith MeCN. The resulting solid was collected via filtration and dried toaffordN-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(74 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 9.10 (s, 1H),8.55 (s, 1H), 8.28 (d, J=2.4 Hz, 1H), 7.92 (s, 1H), 7.65 (s, 1H), 7.59(s, 1H), 7.36 (s, 1H), 6.78 (d, J=2.8 Hz, 1H), 3.93 (m, 3H), 3.82 (m,2H), 3.48 (m, 2H), 3.40 (m, 2H), 2.51 (s, 3H), 2.26 (s, 3H), 1.73 (m,2H), 1.64 (m, 2H); MS (ESI) m/z: 489.2 (M+H⁺).

Example 55

A solution of imidazolidin-2-one (0.75 g, 8.71 mmol) in DMF (17 mL) wastreated drop-wise with LiHMDS (1M THF, 10.45 mL, 10.45 mmol), stirredfor 2 h, treated with bromoacetonitrile (0.607 mL, 8.71 mmol) and heatedat 45° C. overnight. The mixture was cooled to RT, treated with satd.NH₄Cl, extracted with EtOAc (4×) and the combined organics were washedwith brine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/DCM) to afford2-(2-oxoimidazolidin-1-yl)acetonitrile (65 mg, 6%). ¹H NMR (400 MHz,DMSO-d₆): δ 6.38 (s, 1H), 4.66 (s, 2H), 3.98-3.93 (m, 2H), 3.91-3.86 (m,2H); MS (ESI) m/z: 126.1 (M+H⁺).

A 0° C. solution of phosgene (15% in toluene, 1.37 mL, 1.948 mmol) inDCM (5 mL) was treated drop-wise with a solution of2-(2-oxoimidazolidin-1-yl)acetonitrile (0.065 g, 0.519 mmol) andpyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmed to RT, stirred for 2h, then concentrated to dryness. The residue was dissolved in DCM (5mL), cooled to 0° C., treated with a solution of Example A2 (0.069 g,0.260 mmol) and pyridine (0.2 mL) in DCM (5 mL), warmed to RT andstirred for 3 h. The mixture was treated with satd. NaHCO₃, extractedwith DCM (3×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/EtOAc) to afford3-(cyanomethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(25 mg, 22%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.69 (s, 1H), 8.37 (d, J=5.7Hz, 1H), 8.25-8.24 (m, 2H), 8.07 (d, J=9.0 Hz, 1H), 7.96 (d, J=0.7 Hz,1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.23 (d, J=2.4 Hz, 1H), 6.70 (dd,J=5.7, 2.4 Hz, 1H), 4.47 (s, 2H), 3.93-3.84 (m, 5H), 3.54 (t, J=8.2 Hz,2H); MS (ESI) m/z: 419.2 (M+H⁺).

Example 56

A 0° C. solution of phosgene (15% in toluene, 2.0 mL, 2.84 mmol) in DCM(5 mL) was treated drop-wise with a solution of Example B19 (88 mg,0.523 mmol) and pyridine (110 mg, 1.395 mmol) in DCM (5 mL), warmed toRT, stirred for 1 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A9 (103 mg, 0.349 mmol) and pyridine (110 mg, 1.395 mmol) in DCM(5 mL), warmed to RT and stirred overnight. The mixture was concentratedto dryness and purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA). The organics were removed under reduced pressure and theaqueous residue was treated with satd. NaHCO₃ and extracted with EtOAc(3×). The combined organics were washed with brine, dried over Na₂SO₄and concentrated to dryness to affordN-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(101 mg, 59%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.71 (s, 1H), 8.35 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.62(d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H),4.11 (q, J=9.6 Hz, 2H), 3.88-3.86 (m, 2H), 3.84 (s, 3H), 3.60 (t, J=8.2Hz, 2H), 2.57 (q, J=7.5 Hz, 2H), 1.11 (t, J=7.5 Hz, 3H); MS (ESI) m/z:490.2 (M+H⁺).

Example 57

A 0° C. solution of phosgene (15% in toluene, 2.19 mmol, 3.12 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B14 (90 mg,0.584 mmol) and pyridine (123 mg, 1.395 mmol) in DCM (5 mL), warmed toRT, stirred for 1 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A9 (115 mg, 0.389 mmol) and pyridine (123 mg, 1.558 mmol) in DCM(5 mL), warmed to RT and stirred overnight. The mixture was concentratedto dryness and purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA). The organics were removed under reduced pressure and theaqueous residue was treated with satd. NaHCO₃ and extracted with EtOAc(3×). The combined organics were washed with brine, dried over Na₂SO₄and concentrated to dryness to afford3-cyclopentyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(118 mg, 63%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.34 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.60(d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H),4.19 (t, J=7.4 Hz, 1H), 3.84 (s, 3H), 3.80 (t, J=8.2 Hz, 2H), 3.45 (t,J=8.2 Hz, 2H), 2.56 (q, J=7.5 Hz, 2H), 1.78 (d, J=10.8 Hz, 2H),1.67-1.52 (br m, 6H), 1.11 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 476.2(M+H⁺).

Example 58

A 0° C. solution of phosgene (15% in toluene, 2.87 mmol, 4.06 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B20 (96 mg,0.762 mmol) and pyridine (161 mg, 2.032 mmol) in DCM (5 mL), warmed toRT, stirred for 1 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A9 (150 mg, 0.508 mmol) and pyridine (161 mg, 2.032 mmol) in DCM(5 mL), warmed to RT and stirred overnight. The mixture was concentratedto dryness and purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA). The organics were removed under reduced pressure and theaqueous residue was treated with satd. NaHCO₃ and extracted with EtOAc(3×). The combined organics were washed with brine, dried over Na₂SO₄and concentrated to dryness to afford3-cyclopropyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(165 mg, 72%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.34 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.60(d, J=8.8 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.4 Hz, 1H),3.84 (s, 3H), 3.74-3.73 (m, 2H), 3.41 (t, J=8.2 Hz, 2H), 2.58-2.57 (m,3H), 1.11 (t, J=7.5 Hz, 3H), 0.71 (d, J=5.3 Hz, 4H); MS (ESI) m/z: 448.2(M+H⁺).

Example 59

A mixture of (R)-1-methoxypropan-2-amine hydrochloride (500 mg, 3.98mmol) and pyridine (315 mg, 3.98 mmol) in THF (15 mL) was treateddrop-wise with 2-chloroethylisocyanate (420 mg, 3.98 mmol) and stirredat RT overnight. The mixture was concentrated to dryness, partitionedbetween EtOAc and brine and the organic layer dried over Na₂SO₄ andconcentrated to dryness to afford(S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea (393 mg, 50%). ¹H NMR(400 MHz, DMSO-d₆): δ 6.08 (s, 1H), 5.93 (d, J=8.1 Hz, 1H), 3.71 (m,1H), 3.56-3.51 (m, 3H), 3.30-3.23 (m, 3H), 3.22 (s, 3H), 0.98 (d, J=6.7Hz, 3H).

A −20° C. solution of (S)-1-(2-chloroethyl)-3-(1-methoxypropan-2-yl)urea(393 mg, 2.019 mmol) in THF (10 mL) was treated portion-wise with NaH(60% in mineral oil, 178 mg, 4.44 mmol), warmed to RT and stirredovernight. The mixture was treated with EtOAc, washed with water, thenbrine, dried over Na₂SO₄ and concentrated to dryness to afford crude(R)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (100% yield assumed)which was used without further purification. MS (ESI) m/z: 159.1 (M+H⁺).

Phosgene (15% in toluene, 1.75 mL, 2.449 mmol) was treated with asolution of (R)-1-(1-methoxypropan-2-yl)imidazolidin-2-one (155 mg,0.980 mmol) and pyridine (116 mg, 1.470 mmol) in DCM (2 mL), stirred atRT for 15 min, then concentrated to dryness. The residue was dissolvedin DCM (2 mL), treated with a solution of Example A2 (131 mg, 0.490mmol) and TEA (248 mg, 2.449 mmol) in DCM (2 mL) and stirred at RT for 4h. The mixture was treated with EtOAc, washed with satd. NaHCO₃, thenbrine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/EtOAc) to afford(R)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(38 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s, 1H), 8.37 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 8.22-8.21 (m, 1H), 8.06-8.05 (m, 1H), 7.95 (d,J=0.7 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H),6.69 (dd, J=5.7, 2.4 Hz, 1H), 4.10-4.09 (m, 1H), 3.84 (s, 3H), 3.81-3.79(m, 2H), 3.40-3.39 (m, 4H), 3.26 (s, 3H), 1.09 (d, J=6.9 Hz, 3H); MS(ESI) m/z: 452.2 (M+H⁺).

Example 60

A 0° C. solution of phosgene (15% in toluene, 0.650 mL, 0.911 mmol) inDCM (8 mL) was treated with a solution of Example B1 (0.135 g, 0.793mmol) and pyridine (0.080 mL, 0.991 mmol) in DCM (2 mL), stirred for 0.5h, then warmed to RT and concentrated to dryness. The residue wasdissolved in DCM (2 mL), added to a solution of Example A11 (0.200 g,0.703 mmol) and pyridine (0.06 mL, 0.743 mmol) in DCM (5 mL) and stirredat RT overnight. The mixture was treated with satd. NaHCO₃, extractedwith EtOAc (3×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/EtOAc). The material was re-purified via silica gel chromatography(MeOH/DCM) to affordN-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(63 mg, 19%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.97 (s, 1H), 8.40 (d, J=5.8Hz, 1H), 8.32 (s, 1H), 8.25-8.24 (m, 1H), 8.07-8.06 (m, 1H), 7.74 (dd,J=9.0, 2.9 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 6.80 (dd, J=5.8, 2.4 Hz,1H), 3.93-3.78 (m, 5H), 3.48-3.35 (m, 4H), 2.65 (s, 3H), 1.77-1.65 (m,2H), 1.62-1.58 (m, 2H); MS (ESI) m/z: 481.1 (M+H⁺).

Example 61

A 0° C. solution of phosgene (15% in toluene, 1.41 mL, 2.003 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B18 (61 mg,0.534 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmed toRT, stirred for 2 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A12 (0.10 g, 0.267 mmol), pyridine (0.2 mL, 2.473 mmol) and DIEA(0.2 mL, 1.145 mmol) in DCM (5 mL), warmed to RT and stirred for 3 h.The mixture was treated with satd. NaHCO₃, extracted with EtOAc (3×) andthe combined organics were washed with 1N NaOH, then brine, dried overNa₂SO₄ and concentrated to dryness. The material was treated with EtOAcand the resulting solid collected via filtration to afford3-ethyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(35 mg, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 8.50 (d, J=5.6Hz, 1H), 7.96 (d, J=8.1 Hz, 2H), 7.91 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.9Hz, 1H), 7.41 (d, J=2.4 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.75 (dd,J=5.7, 2.4 Hz, 1H), 3.80 (m, 2H), 3.46 (m, 2H), 3.26 (m, 2H), 3.11 (brm, 2H), 2.62 (br m, 2H), 2.43 (s, 3H), 2.25 (s, 3H), 1.89-1.68 (m, 5H),1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 515.3 (M+H⁺).

Example 62

A 0° C. solution of phosgene (15% in toluene, 0.341 mL, 0.478 mmol) inDCM (2 mL) was treated with a solution of Example B3 (0.060 g, 0.416mmol) and pyridine (0.042 mL, 0.520 mmol) in DCM (0.5 mL), stirred for0.5 h, then warmed to RT and concentrated to dryness. The residue wasdissolved in DCM (2 mL), added to a solution of Example A11 (0.100 g,0.352 mmol) and pyridine (0.06 mL, 0.743 mmol) in DCM (5 mL) and stirredat RT for 1 h. The mixture was treated with water, extracted with DCM(3×) and the combined organics were dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/EtOAc) toafford3-(2-methoxyethyl)-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(47 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s, 1H), 8.40 (d, J=5.8Hz, 1H), 8.32 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H),7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 6.80 (dd, J=5.8,2.4 Hz, 1H), 3.83-3.78 (m, 2H), 3.53-3.47 (m, 4H), 3.41-3.37 (m, 2H),3.26 (s, 3H), 2.65 (s, 3H); MS (ESI) m/z: 455.2 (M+H⁺).

Example 63

A mixture of Example A13 (0.5 g, 2.002 mmol),2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.570g, 2.60 mmol) and K₂CO₃ (0.720 g, 5.21 mmol) in dioxane (17 mL) andwater (3 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (0.23 g, 0.199mmol) and heated at 85° C. overnight. The mixture was cooled to RT,diluted with EtOAc and the solids removed via filtration throughdiatomaceous earth. The filtrate was concentrated to dryness, purifiedvia silica gel chromatography (MeOH/DCM), then further purified viareverse-phase chromatography (MeCN/H₂O with 0.1% TFA). The material wastreated with MeCN, heated, then cooled to RT and the solid collected viafiltration to afford6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (320 mg,52%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.07 (d, J=2.4 Hz, 1H), 8.48 (d,J=5.7 Hz, 1H), 8.25 (dd, J=8.1, 2.4 Hz, 1H), 7.51 (d, J=2.4 Hz, 1H),7.33 (d, J=8.1 Hz, 1H), 7.20 (d, J=8.7 Hz, 1H), 6.68 (dd, J=5.7, 2.4 Hz,1H), 6.36 (d, J=8.7 Hz, 1H), 5.96-5.94 (m, 2H), 2.50 (s, 3H), 2.41 (q,J=7.5 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 307.2 (M+H⁺).

A 0° C. solution of Example B1 (0.19 g, 1.116 mmol) and pyridine (0.26mL, 3.21 mmol) in DCM (5 mL) was treated drop-wise with phosgene (20% intoluene, 1.4 mL, 2.65 mmol) and warmed to RT over 0.5 h. The mixture wastreated slowly with a solution of6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-amine (0.16 g,0.522 mmol) and pyridine (0.16 mL, 1.978 mmol) in DCM (5 mL) and stirredat RT overnight. The mixture was treated with satd. NaHCO₃, extractedwith EtOAc (4×) and the combined organics were dried over MgSO₄,concentrated to dryness, purified via silica gel chromatography(MeOH/DCM), then re-purified via reverse-phase chromatography (MeCN/H₂Owith 0.1% TFA). The combined fractions were treated with satd. NaHCO₃,extracted with DCM (5×) and the combined organics were dried over MgSO₄and concentrated to dryness to affordN-(6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(19 mg, 7%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.93 (s, 1H), 9.09 (d, J=2.4Hz, 1H), 8.52 (d, J=5.7 Hz, 1H), 8.28 (dd, J=8.1, 2.4 Hz, 1H), 7.90 (d,J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.59 (d, J=2.4 Hz, 1H), 7.33 (d,J=8.2 Hz, 1H), 6.77 (dd, J=5.7, 2.4 Hz, 1H), 3.94-3.84 (m, 3H),3.83-3.79 (m, 2H), 3.46 (t, J=8.2 Hz, 2H), 3.38 (t, J=11.6 Hz, 2H), 2.58(q, J=7.5 Hz, 2H), 2.50 (s, 3H), 1.72 (dd, J=12.3, 4.5 Hz, 2H), 1.62 (s,2H), 1.12 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 503.3 (M+H⁺).

Example 64

A mixture of Example A13 (0.5 g, 2.002 mmol),2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.570g, 2.60 mmol) and K₂CO₃ (0.720 g, 5.21 mmol) in dioxane (17 mL) andwater (3 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (0.23 g, 0.199mmol) and heated at 85° C. overnight. The mixture was cooled to RT,diluted with EtOAc and the solids removed via filtration throughdiatomaceous earth. The filtrate was concentrated to dryness, purifiedtwice via silica gel chromatography (MeOH/DCM), then further purifiedvia reverse-phase chromatography (MeCN/H₂O with 0.1% TFA). Combinedfractions were neutralized, pooled and concentrated to dryness. Thematerial was treated with MeCN, heated, then cooled to RT and the solidcollected via filtration to afford6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (260 mg,42%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.52 (m, 2H), 7.88 (s, 1H), 7.77 (d,J=5.4 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 6.76 (dd,J=5.7, 2.4 Hz, 1H), 6.36 (d, J=8.7 Hz, 1H), 5.98-5.96 (m, 2H), 2.53 (s,3H), 2.40 (q, J=7.6 Hz, 2H), 1.05 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 307.2(M+H⁺).

A 0° C. solution of Example B1 (0.19 g, 1.116 mmol) and pyridine (0.26mL, 3.21 mmol) in DCM (5 mL) was treated drop-wise with phosgene (20% intoluene, 1.4 mL, 2.65 mmol), warmed to RT over 0.5 h, then treatedslowly with a solution of6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-amine (0.13 g,0.424 mmol) and pyridine (0.16 mL, 1.978 mmol) in DCM (5 mL) and stirredat RT overnight. The mixture was treated with satd. NaHCO₃, extractedwith EtOAc (4×) and the combined organics were dried over MgSO₄,concentrated to dryness, purified via silica gel chromatography(MeOH/DCM), then re-purified via reverse-phase chromatography (MeCN/H₂Owith 0.1% TFA). The organics were removed under reduced pressure, theaqueous residue treated with satd. NaHCO₃, extracted with DCM (5×) andthe combined organics were dried over MgSO₄ and concentrated to drynessto affordN-(6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(8 mg, 4%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.93 (s, 1H), 8.56 (d, J=5.7Hz, 1H), 8.52 (d, J=5.3 Hz, 1H), 7.93-7.89 (m, 2H), 7.67 (d, J=2.4 Hz,1H), 7.68-7.66 (m, 1H), 7.64 (s, 1H), 6.86 (dd, J=5.7, 2.4 Hz, 1H),3.94-3.78 (m, 5H), 3.49-3.34 (m, 4H), 2.58 (q, J=7.5 Hz, 2H), 2.53 (s,3H), 1.78-1.66 (m, 2H), 1.64-1.57 (m, 2H), 1.12 (t, J=7.5 Hz, 3H); MS(ESI) m/z: 503.3 (M+H⁺).

Example 65

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B20 (0.063 g, 0.503 mmol) in DCM (5 mL), stirred at RTfor 1.5 h, then concentrated to dryness. The residue was dissolved inDCM (5 mL), cooled to 0° C., treated with a solution of Example A14 (0.1g, 0.335 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RT andstirred overnight. The mixture was treated with EtOAc, washed with satd.NaHCO₃, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via reverse-phase chromatography (MeCN/H₂O with 0.1% TFA). Thecombined fractions were treated with satd. NaHCO₃, extracted with EtOAcand the organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford3-cyclopropyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(70 mg, 46%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.38 (d, J=5.8Hz, 1H), 8.33 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H),7.56 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.8, 2.4 Hz, 1H), 3.75 (m, 2H), 3.41(m, 2H), 2.65 (s, 3H), 2.60 (m, 1H), 2.25 (s, 3H), 0.71 (m, 4H); MS(ESI) m/z: 451.2 (M+H⁺).

Example 66

A 0° C. solution of phosgene (15% in toluene, 0.849 mL, 1.190 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B1 (0.150 g,0.881 mmol) and pyridine (0.10 mL, 1.234 mmol) in DCM (2 mL), stirredfor 0.5 h, then concentrated to dryness. The residue was dissolved inDCM (1 mL), added to a solution of Example A14 (0.110 g, 0.369 mmol) andpyridine (0.044 mL, 0.542 mmol) in DCM (3 mL) and stirred at RTovernight. The mixture was treated with satd. NaHCO₃, the layersseparated and the aqueous layer was extracted with additional DCM (3×).The combined organics were dried over Na₂SO₄, concentrated to drynessand purified via silica gel chromatography (MeOH/EtOAc) to affordN-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(141 mg, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.38 (d,J=5.8 Hz, 1H), 8.32 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz,1H), 7.55 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.8, 2.4 Hz, 1H), 3.94-3.77 (m,5H), 3.49-3.34 (m, 4H), 2.65 (s, 3H), 2.24 (s, 3H), 1.77-1.66 (m, 2H),1.63-1.57 (m, 2H); MS (ESI) m/z: 495.2 (M+H⁺).

Example 67

A 0° C. solution of phosgene (15% in toluene, 1.00 mL, 1.405 mmol) inDCM (10 mL) was treated drop-wise with a solution of Example B3 (0.150g, 1.040 mmol) and pyridine (0.118 mL, 1.457 mmol) in DCM (2 mL),stirred for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (1 mL), added to a solution of Example A14 (0.110 g,0.369 mmol) and pyridine (0.057 mL, 0.71 mmol) in DCM (3 mL) and stirredat RT overnight. The mixture was treated with satd. NaHCO₃, the layersseparated and the aqueous layer was extracted with additional DCM (3×).The combined organics were dried over Na₂SO₄, concentrated to drynessand purified via silica gel chromatography (MeOH/EtOAc). The materialwas lyophilized and dried, treated with toluene, sonicated andconcentrated to dryness to afford3-(2-methoxyethyl)-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(91 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s, 1H), 8.38 (d, J=5.8Hz, 1H), 8.32 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H),7.55 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.8, 2.4 Hz, 1H), 3.83-3.77 (m, 2H),3.54-3.47 (m, 4H), 3.41-3.36 (m, 2H), 3.26 (s, 3H), 2.65 (s, 3H), 2.25(s, 3H); MS (ESI) m/z: 469.2 (M+H⁺).

Example 68

A mixture of Example A6 (0.676 g, 2.55 mmol),1-methyl-4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)piperazine(1 g, 3.31 mmol), K₂CO₃ (1.055 g, 7.64 mmol) and Pd(PPh₃)₄ (0.147 g,0.127 mmol) in dioxane (8 mL) was sparged with Ar and heated at 90° C.overnight. The mixture was cooled to RT, treated with brine, extractedwith EtOAc (4×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to afford1-methyl-4-(4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)phenyl)piperazine(333 mg, 32%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.55 (d, J=5.6 Hz, 1H), 8.22(d, J=8.7 Hz, 1H), 7.95 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.7 Hz, 1H), 7.58(d, J=2.3 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.94 (dd, J=5.6, 2.3 Hz, 1H),3.24-3.18 (m, 4H), 2.52 (s, 3H), 2.45-2.41 (m, 4H), 2.21 (s, 3H); MS(ESI) m/z: 406.2 (M+H⁺).

A solution of1-methyl-4-(4-(4-((2-methyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)phenyl)piperazine(0.333 g, 0.821 mmol) in MeOH (20 mL) was treated with 10% Pd/C (50% w/wwater, 0.087 g, 0.082 mmol) and hydrogenated (1 atm) overnight. Thesolids were removed via filtration through diatomaceous earth, washedwith MeOH and the filtrate concentrated to dryness to afford6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine(247 mg, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.38 (d, J=5.7 Hz, 1H), 7.85(d, J=8.8 Hz, 2H), 7.21-7.20 (m, 2H), 6.98 (d, J=8.8 Hz, 2H), 6.57 (dd,J=5.6, 2.4 Hz, 1H), 6.35 (d, J=8.7 Hz, 1H), 5.94 (s, 2H), 3.20 (t, J=4.7Hz, 4H), 2.45 (s, 4H), 2.22 (s, 3H), 2.07 (s, 3H); MS (ESI) m/z: 376.2(M+H⁺).

A 0° C. solution of phosgene (15% in toluene, 1.41 mL, 2.003 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B18 (61 mg,0.534 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmed toRT, stirred for 2 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution of6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-amine(0.10 g, 0.266 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (5 mL), warmedto RT and stirred overnight. The mixture was treated with 1N NaOH,extracted with EtOAc (3×) and the combined organics were washed with 1NNaOH, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via reverse-phase chromatography (MeCN/H₂O with 0.1% TFA). Theorganics were removed under reduced pressure and the aqueous residue wastreated with K₂CO₃ and extracted with 5:1 DCM/THF (3×). The combinedorganics were dried over Na₂SO₄ and concentrated to dryness to afford3-ethyl-N-(6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(54 mg, 39%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.42 (d, J=5.6Hz, 1H), 7.92-7.86 (m, 3H), 7.62 (d, J=8.9 Hz, 1H), 7.32 (d, J=2.4 Hz,1H), 6.97 (d, J=8.8 Hz, 2H), 6.63 (dd, J=5.7, 2.3 Hz, 1H), 3.80 (t,J=8.3 Hz, 2H), 3.46 (t, J=8.2 Hz, 2H), 3.26-3.25 (m, 2H), 3.20 (s, 4H),2.43 (s, 4H), 2.25 (s, 3H), 2.21 (s, 3H), 1.09 (t, J=7.2 Hz, 3H); MS(ESI) m/z: 516.3 (M+H⁺).

Example 69

A solution of phosgene (15% in toluene, 0.928 g, 1.407 mmol) was treatedwith a solution of Example B18 (0.080 g, 0.703 mmol) and pyridine (0.028mL, 0.352 mmol) in DCM (3 mL), stirred at RT for 15 min, thenconcentrated to dryness. The residue was treated with a solution ofExample A11 (0.1 g, 0.352 mmol) and TEA (0.178 g, 1.758 mmol) in DCM (3mL) and stirred at RT for 1 h. The mixture was treated with water,extracted with DCM (2×) and the combined organics were washed withbrine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/DCM). The material was further purifiedvia reverse-phase chromatography (MeCN/H₂O with 0.1% TFA); combinedfractions were treated with satd. NaHCO₃, extracted with EtOAc (2×) andthe combined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford3-ethyl-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(72 mg, 48%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.99 (s, 1H), 8.40 (d, J=5.8Hz, 1H), 8.32 (s, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.07 (d, J=9.0 Hz, 1 H),7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.60 (d, J=2.4 Hz, 1H), 6.80 (dd, J=5.8,2.4 Hz, 1H), 3.80-3.79 (m, 2H), 3.46 (m, 2H), 3.26 (q, J=7.0 Hz, 2H),2.65 (s, 3H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 425.1 (M+H⁺).

Example 70

A solution of phosgene (15% in toluene, 1.105 g, 1.676 mmol) was treatedwith a solution of Example B18 (0.057 g, 0.503 mmol) and pyridine (0.136mL, 1.676 mmol) in DCM (3 mL), stirred at RT for 15 min, thenconcentrated to dryness. The residue was treated with a solution ofExample A14 (0.1 g, 0.335 mmol) and TEA (0.140 mL, 1.005 mmol) in DCM (3mL) and stirred at RT for 1 h. The mixture was treated with water,extracted with DCM (2×) and the combined organics were washed withbrine, dried over Na₂SO₄, concentrated to dryness and purifiedreverse-phase chromatography (MeCN/H₂O with 0.1% TFA). The combinedfractions were treated with satd. NaHCO₃, extracted with EtOAc (2×) andthe combined organics were washed with brine, dried over Na₂SO₄ andconcentrated to dryness to afford3-ethyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(101 mg, 69%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (s, 1H), 8.38 (d,J=5.8 Hz, 1H), 8.32 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.8 Hz,1H), 7.55 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.8, 2.4 Hz, 1H), 3.80-3.79 (m,2H), 3.46-3.45 (m, 2H), 3.25 (q, J=7.2 Hz, 2H), 2.65 (s, 3H), 2.24 (s,3H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 439.2 (M+H⁺).

Example 71

A 0° C. solution of phosgene (15% in toluene, 268 mg, 0.593 mmol) in DCM(2 mL) was treated drop-wise with a solution of Example B20 (75 mg,0.593 mmol) and pyridine (107 mg, 1.354 mmol) in DCM (2 mL), warmed toRT, stirred for 1 h, then concentrated to dryness. The residue wasdissolved in DCM (2 mL), cooled to 0° C., treated with a solution ofExample A15 (100 mg, 0.339 mmol) and pyridine (107 mg, 1.354 mmol) inDCM (2 mL), warmed to RT and stirred overnight. The mixture was treatedwith EtOAc, washed with 50% satd. NaHCO₃, then brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/EtOAc) to afford3-cyclopropyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(45 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.82 (s, 1H), 8.32 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.12 (d, J=2.4 Hz,1H), 6.50 (dd, J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 3.76-3.71 (m, 2H),3.44-3.38 (m, 2H), 2.61-2.55 (m, 1H), 2.17 (s, 3H), 2.09 (s, 3H), 0.70(d, J=5.4 Hz, 4H); MS (ESI) m/z: 448.2 (M+H⁺).

Example 72

A 0° C. solution of phosgene (15% in toluene, 1.19 mL, 1.693 mmol) inDCM (3 mL) was treated drop-wise with a solution of Example B14 (91 mg,0.593 mmol) and pyridine (107 mg, 1.354 mmol) in DCM (2 mL), warmed toRT, stirred for 1 h, then concentrated to dryness. The residue wasdissolved in DCM (3 mL), cooled to 0° C., treated with a solution ofExample A15 (100 mg, 0.339 mmol) and pyridine (107 mg, 1.354 mmol) inDCM (2 mL), warmed to RT and stirred overnight. The mixture wasconcentrated to dryness and purified via reverse-phase chromatography(MeCN/H₂O with 0.1% TFA). The organics were removed under reducedpressure and the aqueous residue was treated with satd. NaHCO₃, andallowed to stand for 0.5 h. The resulting solid was collected viafiltration, washed with water and dried to afford3-cyclopentyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(61 mg, 37%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.85 (s, 1H), 8.32 (d, J=5.7Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.83 (s, 1H), 7.12 (d, J=2.4 Hz,1H), 6.50 (dd, J=5.7, 2.4 Hz, 1H), 4.18 (t, J=7.6 Hz, 1H), 3.84 (s, 3H),3.79 (t, J=8.2 Hz, 2H), 3.44 (t, J=8.2 Hz, 2H), 2.16 (s, 3H), 2.09 (s,3H), 1.69-1.60 (m, 8H); MS (ESI) m/z: 476.3 (M+H⁺).

Example 73

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and 1-methylimidazolidin-2-one (0.038 g, 0.377 mmol) in DCM (5mL), warmed to RT, stirred for 1.5 h, then concentrated to dryness. Theresidue was dissolved in DCM (5 mL), cooled to 0° C., treated with asolution of Example A14 (0.075 g, 0.251 mmol) and pyridine (0.1 mL) inDCM (5 mL), warmed to RT and stirred overnight. The mixture was treatedwith satd. NaHCO₃, extracted with DCM (2×) and the combined organicswere dried over Na₂SO₄, concentrated to dryness and purified viareverse-phase chromatography (MeCN/H₂O with 0.1% TFA). The combinedfractions were treated with satd. NaHCO₃, extracted with EtOAc and theorganic layer was dried over Na₂SO₄ and concentrated to dryness toafford3-methyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine1-carboxamide (56 mg, 53%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H),8.38 (d, J=5.8 Hz, 1H), 8.33 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.63 (d,J=8.8 Hz, 1H), 7.56 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.8, 2.4 Hz, 1H),3.80 (m, 2H), 3.45 (m, 2H), 2.81 (s, 3H), 2.65 (s, 3H), 2.25 (s, 3H); MS(ESI) m/z: 425.2 (M+H⁺).

Example 74

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B19 (0.063 g, 0.377 mmol) in DCM (5 mL), warmed to RT,stirred for 1.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A14 (0.075 g, 0.251 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred overnight. The mixture was treated with satd.NaHCO₃, extracted with DCM (2×) and the combined organics were driedover Na₂SO₄, concentrated to dryness and purified via reverse-phasechromatography (MeCN/H₂O with 0.1% TFA). The combined fractions weretreated with satd. NaHCO₃, extracted with EtOAc (2×) and the combinedorganics were dried over Na₂SO₄ and concentrated to dryness to affordN-(6-methyl-5-((2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(68 mg, 54%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.70 (s, 1H), 8.39 (d, J=5.8Hz, 1H), 8.33 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.65 (d, J=8.8 Hz, 1H),7.56 (d, J=2.4 Hz, 1H), 6.71 (dd, J=5.8, 2.4 Hz, 1H), 4.11 (q, J=9.6 Hz,2H), 3.89 (m, 2H), 3.60 (m 2H), 2.65 (s, 3H), 2.26 (s, 3H); MS (ESI)m/z: 493.1 (M+H⁺).

Example 75

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B14 (0.058 g, 0.377 mmol) in DCM (5 mL), warmed to RT,stirred for 1.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A14 (0.075 g, 0.251 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred overnight. The mixture was treated with satd.NaHCO₃, extracted with DCM (2×) and the combined organics were driedover Na₂SO₄, concentrated to dryness and purified via reverse-phasechromatography (MeCN/H₂O with 0.1% TFA). The combined fractions weretreated with satd. NaHCO₃, extracted with EtOAc (2×) and the combinedorganics were dried over Na₂SO₄ and concentrated to dryness to afford3-cyclopentyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(40 mg, 33%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.38 (d, J=5.8Hz, 1H), 8.33 (s, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H),7.56 (d, J=2.4 Hz, 1H), 6.70 (dd, J=5.8, 2.4 Hz, 1H), 4.19 (m, 1H), 3.80(m, 2H), 3.45 (m, 2H), 2.65 (s, 3H), 2.25 (s, 3H), 1.78 (m, 2H),1.67-1.52 (m, 6H); MS (ESI) m/z: 479.2 (M+H⁺).

Example 76

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5

mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B19 (0.066 g, 0.393 mmol) in DCM (5 mL), warmed to RT,stirred for 1.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A16 (0.070 g, 0.262 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred overnight. The mixture was treated with satd.NaHCO₃, extracted with DCM (2×) and the combined organics were driedover Na₂SO₄ and concentrated to dryness. The material was treated withEtOAc and the resulting solid collected via filtration and dried toaffordN-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(66 mg, 54%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (s, 1H), 8.41 (d, J=1.4Hz, 1H), 8.34 (d, J=5.8 Hz, 1H), 8.29 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.1Hz, 1H), 7.78 (dd, J=9.1, 2.9 Hz, 1H), 7.65 (s, 1H), 7.40 (d, J=2.2 Hz,1H), 6.84 (dd, J=5.8, 2.2 Hz, 1H), 4.12 (q, J=9.6 Hz, 2H), 3.89 (m, 2H),3.60 (m, 2H), 2.14 (d, J=1.0 Hz, 3H); MS (ESI) m/z: 462.2 (M+H⁺).

Example 77

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B1 (0.067 g, 0.393 mmol) in DCM (5 mL), warmed to RT,stirred for 1.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A16 (0.070 g, 0.262 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred overnight. The mixture was treated with satd.NaHCO₃, extracted with DCM (2×) and the combined organics were driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM). The material was treated with EtOAc, allowedto stand at RT and the resulting solid collected via filtration anddried to affordN-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(53 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.99 (s, 1H), 8.40 (d, J=1.4Hz, 1H), 8.33 (d, J=5.8 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.1Hz, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (d, J=1.4 Hz, 1H), 7.40 (d,J=2.2 Hz, 1H), 6.83 (dd, J=5.8, 2.2 Hz, 1H), 3.93-3.89 (m, 3H), 3.82 (m,2H), 3.35-3.50 (m, 4H), 2.14 (d, J=1.0 Hz, 3H), 1.72 (m, 2H), 1.60 (m,2H); MS (ESI) m/z: 464.2 (M+H⁺).

Example 78

A mixture of Example A8 (1.35 g, 4.83 mmol), Example C6 (1.874 g, 4.83mmol) and Pd(PPh₃)₄ (279 mg, 0.241 mmol) in toluene (15 mL) was spargedwith Ar and heated at 105° C. overnight. The mixture was cooled to RT,treated with 10% KF and EtOAc and stirred vigorously for 2 h. Themixture was diluted with additional EtOAc, the solids removed viafiltration through diatomaceous earth, the layers of the filtrateseparated and the organic layer washed with satd. NaHCO₃, then brine,dried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to afford5-(4-((2-ethyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)-2-methylthiazole(756 mg, 45%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.50 (d, J=5.7 Hz, 1H), 8.35(s, 1H), 8.24 (d, J=8.7 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.73 (d, J=2.4Hz, 1H), 7.02 (dd, J=5.7, 2.4 Hz, 1H), 2.84 (q, J=7.5 Hz, 2H), 2.65 (s,3H), 1.24 (t, J=7.5 Hz, 3H); MS (ESI) m/z: 343.1 (M+H⁺).

A mixture of5-(4-((2-ethyl-6-nitropyridin-3-yl)oxy)pyridin-2-yl)-2-methylthiazole(756 mg, 2.208 mmol) and 10% Pd/C (50% w/w with water, 235 mg, 0.221mmol) in MeOH (15 mL) was hydrogenated (1 atm) at RT overnight, thenwarmed to 50° C. for 4 h. The mixture was cooled to RT, the solidsremoved via filtration through diatomaceous earth, washed with MeOH andthe filtrate concentrated to dryness to afford6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (79mg, 11%). MS (ESI) m/z: 313.1 (M+H⁺).

A 0° C. solution of phosgene (15% in toluene, 0.88 mL, 1.248 mmol) inDCM (2 mL) was treated drop-wise with a solution of Example B14 (67 mg,0.437 mmol) and pyridine (79 mg, 0.999 mmol) in DCM (1 mL), warmed toRT, stirred for 1 h, then concentrated to dryness. The residue wasdissolved in DCM (1 mL), added to a 0° C. solution of6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (78mg, 0.339 mmol) and pyridine (79 mg, 0.999 mmol) in DCM (2 mL) and THF(1 mL), warmed to RT and stirred overnight. The mixture was concentratedto dryness and purified via silica gel chromatography (EtOAc/Hex) toafford3-cyclopentyl-N-(6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(42 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.37 (d, J=5.8Hz, 1H), 8.32 (s, 1H), 7.90 (d, J=8.8 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H),7.57 (d, J=2.4 Hz, 1H), 6.69 (dd, J=5.8, 2.4 Hz, 1H), 4.18 (t, J=7.6 Hz,1H), 3.80-3.78 (m, 2H), 3.45 (t, J=8.2 Hz, 2H), 2.65 (s, 3H), 2.57 (q,J=7.6 Hz, 2H), 1.78 (d, J=11.0 Hz, 2H), 1.65-1.52 (m, 6H), 1.11 (t,J=7.5 Hz, 3H); MS (ESI) m/z: 493.2 (M+H⁺).

Example 79

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B18 (0.045 g, 0.393 mmol) in DCM (5 mL), warmed to RT,stirred for 1.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A16 (0.070 g, 0.262 mmol) and pyridine (0.1 mL) in DCM (5 mL),warmed to RT and stirred overnight. The mixture was treated with satd.NaHCO₃, extracted with DCM (2×) and the combined organics were driedover Na₂SO₄, concentrated to dryness and purified via reverse-phasechromatography (MeCN/H₂O with 0.1% TFA). The combined fractions weretreated with satd. NaHCO₃, extracted with EtOAc (2×) and the combinedorganics were dried over Na₂SO₄ and concentrated to dryness to afford3-ethyl-N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazocarboxamide (53 mg, 50%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.00 (s, 1H),8.40 (s, 1H), 8.33 (d, J=5.8 Hz, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.09 (d,J=9.0 Hz, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.65 (s, 1H), 7.39 (d,J=2.2 Hz, 1H), 6.83 (dd, J=5.8, 2.2 Hz, 1H), 3.81 (m, 2H), 3.47 (m, 2H),3.27 (m, 2H), 2.14 (d, J=1.0 Hz, 3H), 1.10 (t, J=7.2 Hz, 3H); MS (ESI)m/z: 408.2 (M+H⁺).

Example 80

A mixture of Example C5 (0.150 g, 0.370 mmol), Example C7 (0.145 g,0.480 mmol), K₂CO₃ (0.153 g, 1.109 mmol) and Pd(PPh₃)₄ (0.043 g, 0.037mmol) in dioxane (6 mL) and water (1.5 mL) was sparged with Ar andheated at 90° C. overnight. The mixture was cooled to RT, treated with1N NaOH, extracted with EtOAc (4×) and the combined organics were washedwith brine, dried over Na₂SO₄, concentrated to dryness and purified viasilica gel chromatography (MeOH/DCM) to afford3-(2-methoxyethyl)-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(125 mg, 62%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s, 1H), 8.49 (d,J=5.7 Hz, 1H), 7.92-7.91 (m, 3H), 7.64 (d, J=8.8 Hz, 1H), 7.40 (d, J=2.4Hz, 1H), 7.31 (d, J=8.2 Hz, 2H), 6.75 (dd, J=5.7, 2.4 Hz, 1H), 3.81-3.79(m, 2H), 3.51-3.49 (m, 4H), 3.39 (m, 2H), 3.26 (s, 3H), 2.85 (m, 2H),2.25 (s, 3H), 2.17 (s, 3H), 1.96-1.93 (m, 2H), 1.71-1.66 (m, 5H); MS(ESI) m/z: 545.3 (M+H⁺).

Example 81

A mixture of Example C5 (0.150 g, 0.370 mmol),N-methyl-4-(tributylstannyl)imidazole (0.178 g, 0.480 mmol) andPd(PPh₃)₄ (0.021 g, 0.018 mmol) in toluene (4 mL) was sparged with Arand heated at 105° C. overnight. The mixture was cooled to RT, treatedwith 10% KF and EtOAc, stirred for 2 h and the solids removed viafiltration through diatomaceous earth. The filtrate was extracted withEtOAc (3×) and the combined organics were washed with 10% KF, thenbrine, dried over Na₂SO₄ and concentrated to dryness. The material wastreated with MeCN, sonicated, the solid removed via filtration and thefiltrate concentrated to dryness and purified via silica gelchromatography (MeOH/DCM). The material was suspended in MeCN, sonicatedand the solid collected via filtration. The filtrate was concentrated todryness and further purified via reverse-phase chromatography (MeCN/H₂Owith 0.1% TFA). The organics were removed under reduced pressure, theaqueous residue treated with satd. NaHCO₃, extracted with EtOAc (3×) andthe combined organics were dried over Na₂SO₄, concentrated to drynessand combined with the above-isolated solid to afford3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(61 mg, 36%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s, 1H), 8.35 (d, J=5.7Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.64 (d, J=8.8Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.16 (d, J=2.6 Hz, 1H), 6.74 (dd,J=5.7, 2.6 Hz, 1H), 3.84-3.78 (m, 2H), 3.67 (s, 3H), 3.54-3.47 (m, 4H),3.41-3.37 (m, 2H), 3.26 (s, 3H), 2.23 (s, 3H); MS (ESI) m/z: 452.2(M+H⁺).

Example 82

A 0° C. solution of phosgene (15% in toluene, 2.375 mL, 3.37 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B18 (0.102g, 0.898 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmedto RT, stirred for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A17 (0.12 g, 0.449 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (5mL) and stirred at RT overnight. The mixture was treated with 1N NaOH,extracted with EtOAc (4×) and the combined organics were washed with 1NNaOH, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to afford3-ethyl-N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(150 mg, 82%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.99 (s, 1H), 8.36 (d,J=5.6 Hz, 1H), 8.24 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.75 (dd,J=9.0, 2.9 Hz, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.23(d, J=2.6 Hz, 1H), 6.80 (dd, J=5.7, 2.6 Hz, 1H), 3.81-3.80 (m, 2H), 3.67(s, 3H), 3.46 (t, J=8.2 Hz, 2H), 3.26-3.25 (m, 2H), 1.09 (t, J=7.2 Hz,3H); MS (ESI) m/z: 408.2 (M+H).

Example 83

A 0° C. solution of phosgene (15% in toluene, 2.375 mL, 3.37 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B1 (0.153 g,0.898 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmed toRT, stirred for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A17 (0.12 g, 0.449 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (5mL) and stirred at RT overnight. The mixture was treated with 1N NaOH,extracted with EtOAc (4×) and the combined organics were washed with 1NNaOH, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to affordN-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(180 mg, 87%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s, 1H), 8.36 (d,J=5.7 Hz, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.75 (dd,J=9.0, 2.9 Hz, 1H), 7.67 (d, J=1.3 Hz, 1H), 7.59 (s, 1H), 7.23 (d, J=2.6Hz, 1H), 6.80 (dd, J=5.6, 2.6 Hz, 1H), 3.94-3.87 (m, 3H), 3.84-3.78 (m,2H), 3.67 (s, 3H), 3.48-3.35 (m, 4H), 1.77-1.65 (m, 2H), 1.63-1.56 (m,2H); MS (ESI) m/z: 464.2 (M+H⁺).

Example 84

A 0° C. solution of phosgene (15% in toluene, 2.375 mL, 3.37 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B19 (0.075g, 0.449 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmedto RT, stirred for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A17 (0.12 g, 0.449 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (5mL) and stirred at RT overnight. The mixture was treated with 1N NaOH,extracted with EtOAc (4×) and the combined organics were washed with 1NNaOH, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to affordN-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide(114 mg, 55%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (s, 1H), 8.37 (d,J=5.6 Hz, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.08 (d, J=9.0 Hz, 1H), 7.77 (dd,J=9.0, 2.9 Hz, 1H), 7.68 (d, J=1.4 Hz, 1H), 7.60 (d, J=1.3 Hz, 1H), 7.24(d, J=2.6 Hz, 1H), 6.80 (dd, J=5.7, 2.6 Hz, 1H), 4.11 (q, J=9.6 Hz, 2H),3.88-3.87 (m, 2H), 3.67 (s, 3H), 3.59 (t, J=8.2 Hz, 2H); MS (ESI) m/z:462.2 (M+H⁺).

Example 85

A solution of Example A18 (1.5 g, 5.65 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.527 g, 7.34 mmol) in dioxane (20 mL) was sparged with Ar, treatedwith a solution of K₂CO₃ (1.171 g, 8.47 mmol) in water (5 mL) andPd(PPh₃)₄ (0.326 g, 0.282 mmol) and heated at 80° C. overnight. Themixture was cooled to RT, treated with water, extracted with DCM (4×)and the combined organics were dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to afford4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine(2.3 g, 75%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.48 (s, 1H), 8.43-8.42 (m,2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.30 (d, J=2.4 Hz, 1H), 6.83 (dd,J=5.7, 2.4 Hz, 1H), 3.84 (s, 3H), 2.34 (s, 3H); MS (ESI) m/z: 312.1(M+H⁺).

A solution of4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-2-nitropyridine(2.3 g, 7.39 mmol) in MeOH (37 mL) and THF (37 mL) was treated withNH₄Cl (11.86 g, 222 mmol) followed by the portion-wise addition of zincdust (4.83 g, 73.9 mmol) and the mixture stirred at RT overnight. Themixture was diluted with EtOAc, the solids removed via filtrationthrough diatomaceous earth and the filtrate concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM) to afford4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(1.4 g, 67%). MS (ESI) m/z: 282.1 (M+H⁺).

A 0° C. solution of phosgene (15% in toluene, 2.82 mL, 4.00 mmol) in DCM(3 mL) was treated drop-wise with a solution of1-methyl-2-imidazolidinone (0.107 g, 1.066 mmol) and pyridine (0.2 mL,2.473 mmol) in DCM (3 mL), warmed to RT, stirred for 0.5 h, thenconcentrated to dryness. The residue was dissolved in DCM (3 mL), cooledto 0° C., treated with a solution of4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-amine(0.15 g, 0.533 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (3 mL), warmedto RT and stirred for 3 h. The mixture was treated with satd. NaHCO₃,extracted with DCM (4×) and the combined organics were dried over Na₂SO₄and concentrated to dryness. The material was treated with MeCN and theresulting solid was collected via filtration to afford3-methyl-N-(4-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(116 mg, 52%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.34 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 8.10 (s, 1H), 8.01 (s, 1H), 7.95 (s, 1H),7.16 (d, J=2.4 Hz, 1H), 6.59 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H),3.79-3.78 (m, 2H), 3.45 (t, J=8.2 Hz, 2H), 2.80 (s, 3H), 2.14 (s, 3H);MS (ESI) m/z: 408.2 (M+H⁺).

Example 86

A 0° C. solution of phosgene (15% in toluene, 1.695 mL, 2.403 mmol) inDCM (5 mL) was treated drop-wise with a solution of Example B20 (0.081g, 0.641 mmol) and pyridine (0.2 mL, 2.473 mmol) in DCM (5 mL), warmedto RT, stirred for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (5 mL), cooled to 0° C., treated with a solution ofExample A12 (0.12 g, 0.320 mmol) and DIEA (0.2 mL, 1.145 mmol) in DCM (5mL), warmed to RT and stirred overnight. The mixture was treated with 1NNaOH, extracted with EtOAc (4×) and the combined organics were washedwith 1N NaOH, then brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/DCM. The material wastreated with MTBE, sonicated, stirred vigorously overnight and theresulting solid collected via filtration to afford3-cyclopropyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxocarboxamide (67 mg, 40%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H),8.49 (d, J=5.7 Hz, 1H), 7.92-7.91 (m, 3H), 7.64 (d, J=8.9 Hz, 1H), 7.40(d, J=2.4 Hz, 1H), 7.32 (d, J=8.1 Hz, 2H), 6.75 (dd, J=5.6, 2.4 Hz, 1H),3.75-3.73 (m, 2H), 3.41 (t, J=8.2 Hz, 2H), 2.90-2.88 (m, 2H), 2.58 (m,1H), 2.26 (s, 3H), 2.25 (br s, 3H), 2.04-2.02 (m, 2H), 1.78-1.63 (m,5H), 0.71 (m, 4H); MS (ESI) m/z: 527.3 (M+H⁺).

Example 87

A mixture of Example C3 (0.377 g, 0.873 mmol) and K₂CO₃ (0.362 g, 2.62mmol) in dioxane (4 mL) and water (1 mL) was sparged with Ar, treatedwith 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(0.201 g, 0.917 mmol) and Pd(Ph₃P)₄ (0.101 g, 0.087 mmol), sparged againwith Ar and heated at 80° C. overnight. The mixture was cooled to RT,diluted with EtOAc, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (MeOH/EtOAc). The material wastreated with Et₂O, stirred at RT and the resulting solid collected viafiltration and dried to affordN-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(151 mg, 35%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.56 (d,J=5.6 Hz, 1H), 8.52 (d, J=5.2 Hz, 1H), 7.93-7.88 (m, 2H), 7.79 (dd,J=5.3, 1.6 Hz, 1H), 7.66-7.63 (m, 2H), 6.86 (dd, J=5.6, 2.4 Hz, 1H),3.93-3.77 (m, 5H), 3.49-3.34 (m, 4H), 2.52 (s, 3H), 2.26 (s, 3H),1.78-1.66 (m, 2H), 1.63-1.57 (m, 2H); MS (ESI) m/z: 489.2 (M+H⁺).

Example 88

A 0° C. solution of phosgene (15% in toluene, 5 mL, 7.09 mmol) in DCM (8mL) was treated drop-wise with a solution of Example B18 (0.2 g, 1.752mmol) and pyridine (0.5 mL, 6.18 mmol) in DCM (8 mL), warmed to RT,stirred for 0.5 h, then concentrated to dryness. The residue wasdissolved in DCM (8 mL), cooled to 0° C., treated with a solution ofExample A19 (0.2 g, 0.849 mmol) and DIEA (0.5 mL, 2.86 mmol) in DCM (8mL), warmed to RT and stirred for 3 h. The mixture was treated withsatd. NaHCO₃, extracted with DCM (5×) and the combined organics weredried over Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to affordN-(5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide(300 mg, 94%). MS (ESI) m/z: 376.1 (M+H⁺).

A solution of Pd₂(dba)₃ (0.029 g, 0.032 mmol) and Me₄t-BuXPhos (0.034 g,0.072 mmol) in toluene (0.6 mL) and dioxane (1.2 mL) was heated at 120°C. for 3 min, cooled to RT, added to a degassed suspension ofN-(5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide(0.3 g, 0.798 mmol), 4-methyl imidazole (0.085 g, 1.038 mmol) and K₃PO₄(0.339 g, 1.597 mmol) in toluene (1.2 mL) and dioxane (2.4 mL) andheated at 110° C. overnight. The mixture was treated with additionalcatalyst (synthesized from Pd₂(dba)₃ (0.029 g, 0.032 mmol) andMe₄t-BuXPhos (0.034 g, 0.072 mmol) in toluene (0.6 mL) and dioxane (1.2mL) as above) and heated at 110° C. overnight. The mixture was cooled toRT, treated with satd. NaHCO₃, extracted with EtOAc (5×) and thecombined organics were dried over Na₂SO₄, concentrated to dryness andpurified twice via silica gel chromatography (MeOH/DCM). The materialwas further purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA); the organics were removed under reduced pressure and theaqueous residue was treated with satd. NaHCO₃ and extracted with DCM(3×). The combined organics were dried over Na₂SO₄ and concentrated todryness to afford3-ethyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(112 mg, 32%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.93 (s, 1H), 8.39 (d,J=1.4 Hz, 1H), 8.30 (d, J=5.8 Hz, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.64(s, 1H), 7.33 (d, J=2.2 Hz, 1H), 6.73 (dd, J=5.8, 2.2 Hz, 1H), 3.80 (t,J=8.3 Hz, 2H), 3.46 (t, J=8.2 Hz, 2H), 3.26-3.25 (q, J=7.2 Hz, 2H), 2.15(s, 3H), 2.13 (s, 3H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 422.2(M+H⁺).

Example 89

A 0° C. solution of phosgene (15% in toluene, 5 mL, 7.09 mmol) in DCM (8mL) was treated drop-wise with a solution of 1-methyl-2-imidazolidinone(0.2 g, 1.998 mmol) and pyridine (0.5 mL, 6.18 mmol) in DCM (8 mL),warmed to RT, stirred for 0.5 h, then concentrated to dryness. Theresidue was dissolved in DCM (8 mL), cooled to 0° C., treated with asolution of Example A19 (0.2 g, 0.849 mmol) and DIEA (0.5 mL, 2.86 mmol)in DCM (8 mL), warmed to RT and stirred for 3 h. The mixture was treatedwith satd. NaHCO₃, extracted with DCM (5×) and the combined organicswere dried over Na₂SO₄, concentrated to dryness and purified via silicagel chromatography (MeOH/DCM) to affordN-(5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-yl)-3-methyl-2-oxoimidazolidine-1-carboxamide(100 mg, 33%). MS (ESI) m/z: 362.1 (M+H⁺).

A solution of Pd₂(dba)₃ (10.12 mg, 0.011 mmol) and Me₄t-BuXPhos (0.012g, 0.025 mmol) in toluene (0.2 mL) and dioxane (0.4 mL) was heated at120° C. for 3 min, cooled to RT, added to a degassed suspension ofN-(5-((2-chloropyridin-4-yl)oxy)-4-methylpyridin-2-yl)-3-methyl-2-oxoimidazolidine-1-carboxamide(0.1 g, 0.276 mmol), 4-methyl imidazole (0.030 g, 0.359 mmol) and K₃PO₄(0.117 g, 0.553 mmol) in toluene (0.4 mL) and dioxane (0.8 mL) andheated at 110° C. overnight. The mixture was treated with additionalcatalyst (synthesized from Pd₂(dba)₃ (10.12 mg, 0.011 mmol) andMe₄t-BuXPhos (0.012 g, 0.025 mmol) in toluene (0.2 mL) and dioxane (0.4mL) as above) and heated at 110° C. overnight. The mixture was cooled toRT, treated with satd. NaHCO₃, extracted with EtOAc (5×) and thecombined organics were dried over Na₂SO₄, concentrated to dryness andpurified twice via silica gel chromatography (MeOH/DCM). The materialwas treated with MeCN, heated to reflux, cooled to RT and the resultingsolid collected via filtration and dried to afford3-methyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(20 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 8.39 (d, J=1.4Hz, 1H), 8.30 (d, J=5.8 Hz, 1H), 8.13 (s, 1H), 8.02 (s, 1H), 7.64 (t,J=1.3 Hz, 1H), 7.33 (d, J=2.2 Hz, 1H), 6.73 (dd, J=5.8, 2.2 Hz, 1H),3.79-3.78 (m, 2H), 3.46-3.44 (m, 2H), 2.80 (s, 3H), 2.15 (s, 3H), 2.13(s, 3H); MS (ESI) m/z: 408.2 (M+H⁺).

Example 90

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.236mmol) and Example B16 (0.116 g, 0.819 mmol) in DCM (5 mL), warmed to RT,stirred for 1 h, then concentrated to dryness. The residue was dissolvedin DCM (5 mL), cooled to 0° C., treated with a solution of Example A23(0.10 g, 0.409 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RTand stirred overnight. The mixture was treated with satd. NaHCO₃,extracted with EtOAc (3×) and the combined organics were dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex). The material was treated with Et₂O,sonicated and the resulting solid collected via filtration to afford4-((6-(3-(tert-butyl)-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide(138 mg, 81%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.08 (s, 1H), 8.77 (q,J=4.9 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.09 (d,J=9.0 Hz, 1H), 7.76 (dd, J=9.0, 2.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H),7.18 (dd, J=5.6, 2.7 Hz, 1H), 3.73 (m, 2H), 3.52 (m, 2H), 2.78 (d, J=4.9Hz, 3H), 1.37 (s, 9H); MS (ESI) m/z: 413.2 (M+H⁺).

Example 91

A 0° C. mixture of Example A20 (0.200 g, 0.662 mmol) and TEA (0.277 mL,1.985 mmol) in DCM (3 mL) was treated with a solution of Example B2(0.246 g, 1.059 mmol) in THF (5 mL), warmed to RT and stirred for 1 h.The mixture was concentrated to dryness, purified via silica gelchromatography (MeOH/DCM), treated with Et₂O, sonicated and theresulting solid collected via filtration to affordN-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(263 mg, 80%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.94 (s, 1H), 8.37 (d,J=5.7 Hz, 1H), 8.27 (s, 1H), 8.20 (dd, J=12.5, 7.4 Hz, 1H), 7.97 (s,1H), 7.58 (dd, J=11.1, 7.4 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 6.70 (dd,J=5.7, 2.5 Hz, 1H), 3.94-3.77 (m, 8H), 3.47 (t, J=8.2 Hz, 2H), 3.38 (t,J=11.7 Hz, 2H), 1.71 (m, 2H), 1.59 (br d, J=12.4 Hz, 2H); MS (ESI) m/z:499.2 (M+H⁺).

Example 92

A 0° C. suspension of Example A22 (0.100 g, 0.314 mmol) and TEA (0.131mL, 0.941 mmol) in DCM (3 mL) was treated with a thin suspension ofcrude Example B2 (0.117 g, 0.502 mmol) in DCM (4 mL). The mixture waswarmed to RT, stirred overnight, treated with a solution of additionalExample B2 (34 mg, 0.147 mmol) in DCM (2 mL) and stirred for 1 h. Themixture was concentrated to dryness, purified via silica gelchromatography (MeOH/DCM), the resulting solid triturated with MTBE,collected via filtration, rinsed with MTBE and dried to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamideas a white solid (136 mg, 84%). 1H NMR (400 MHz, DMSO-d₆): δ 10.92 (d,J=2.7 Hz, 1H), 8.38-8.37 (m, 2H), 8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H),7.57 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 6.64 (dd, J=5.7, 2.5Hz, 1H), 3.93-3.77 (m, 8H), 3.47 (m, 2H), 3.37 (m, 2H), 1.70 (m, 2H),1.59 (m, 2H); MS (ESI) m/z: 515.2 (M+H⁺).

Example 93

A solution of 1,3-difluoro-2-methyl-benzene (15 g, 0.12 mol) in H₂SO₄(100 mL) was treated drop-wise with 65% HNO₃ (11.4 g, 0.12 mol) at −10°C. and the resultant mixture was stirred for 30 min. The mixture waspoured into ice-water and extracted with EtOAc (3×). The combinedorganic layers were washed with brine, dried over Na₂SO₄ andconcentrated in vacuo to give 1,3-difluoro-2-methyl-4-nitro-benzene (16g, 78%). ¹H NMR (400 MHz, CDCl₃): δ 7.80 (m, 1H), 6.95 (m, 1H), 2.30 (s,3H).

1,3-Difluoro-2-methyl-4-nitro-benzene (16 g, 0.092 mol), benzyl alcohol(10 g, 0.092 mol) and K₂CO₃ (25.3 g, 0.18 mol), were combined in DMF(300 mL) and heated to 100° C. overnight. The mixture was poured intowater and extracted with EtOAc (3×). The combined organic layers werewashed with brine, dried over Na₂SO₄, concentrated in vacuo and purifiedby silica gel chromatography to give1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 33%). ¹H NMR (400MHz, DMSO-d₆): δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08 (d,J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).

A solution of 1-benzyloxy-3-fluoro-2-methyl-4-nitro-benzene (8 g, 0.031mol) in MeOH (100 mL) was treated with Pd/C (10%) and hydrogenated (30psi) for 2 h. The catalyst was removed by filtration, and the filtratewas concentrated in vacuo to afford 4-amino-3-fluoro-2-methyl-phenol(4.2 g, 96% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.61 (s, 1H), 6.36 (m,2H), 4.28 (s, 2H), 1.96 (s, 3H); MS (ESI) m/z: 142.1 [M+H]⁺.

Potassium tert-butoxide (3.5 g, 31 mmol) was added to a solution of4-amino-3-fluoro-2-methyl-phenol (4.2 g, 30 mmol) in DMA, and stirred atRT for 0.5 h. A solution of 2,4-dichloropyridine (4.38 g, 30 mmol) inDMA was added and the mixture was heated at 100° C. overnight. Thereaction mixture was concentrated in vacuo and the residue was dissolvedin EtOAc (200 mL) and filtered through silica gel. The filter cake waswashed with EtOAc, and the combined filtrates were concentrated in vacuoand purified by silica gel chromatography to give4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (3.2 g, 42%yield). ¹H NMR (400 MHz, DMSO-d₆): δ 8.21 (d, J=6.4 Hz, 1H), 6.84 (d,J=2.0 Hz, 1H), 6.81 (dd, J=5.6, 2.4 Hz, 1H), 6.67-6.65 (m, 2H), 5.13 (s,2H), 1.91 (s, 3H); MS (ESI): m/z 253.2 [M+H]⁺.

Using a procedure analogous to Example 95,4-(2-chloro-pyridin-4-yloxy)-2-fluoro-3-methyl-phenylamine (1.0 g, 3.3mmol),1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (1g, 4.8 mmol), Na₂CO₃ (0.84 g, 6.6 mmol) and Pd(PPh₃)₄ (0.25 g, 0.2 mmol)were combined to give2-fluoro-3-methyl-4-[2-(1-methyl-1H-pyrazol-4-yl)-pyridin-4-yloxy]-phenylamine(0.74 g, 75%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.27 (d, J=6.4 Hz, 1H), 8.18(s, 1H), 7.90 (s, 1H), 7.07 (s, 1H), 6.68-6.61 (m, 2H), 6.45 (dd, J=5.6,2.4 Hz, 1H), 5.06 (s, 2H), 3.82 (s, 3H), 1.95 (s, 3H); MS (ESI) m/z:299.2 [M+H]⁺.

Phosgene (20% in toluene, 0.798 mL, 1.508 mmol) was treated drop-wisewith a solution of Example B1 (0.128 g, 0.754 mmol) and pyridine (0.244mL, 3.02 mmol) in DCM (5 mL), stirred at RT for 10 min, thenconcentrated to dryness. The residue was dissolved in DCM (5 mL),treated drop-wise with a solution of2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline(0.15 g, 0.503 mmol) and DIEA (0.527 mL, 3.02 mmol) in DCM (5 mL)stirred at RT for 3 h. The mixture was treated with satd. NaHCO₃,extracted with DCM (3×) and the combined organics were dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to affordN-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(0.188 g, 76%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.76 (d, J=2.7 Hz, 1H),8.33 (d, J=5.7 Hz, 1H), 8.24 (s, 1H), 8.05 (t, J=9.0 Hz, 1H), 7.95 (d,J=0.7 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 6.57 (dd,J=5.7, 2.4 Hz, 1H), 3.93-3.83 (m, 6H), 3.82-3.77 (m, 2H), 3.46 (t, J=8.2Hz, 2H), 3.38 (dd, J=12.6, 10.8 Hz, 2H), 2.05 (d, J=2.0 Hz, 3H), 1.71(m, 2H), 1.59 (br d, J=12.3 Hz, 2H); MS (ESI) m/z: 495.2 (M+H⁺).

Example 94

A mixture of Example C8 (0.200 g, 0.426 mmol),4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.124 g,0.639 mmol) and K₂CO₃ (0.177 g, 1.279 mmol) in dioxane (4 mL) and water(1 mL) was sparged with Ar, treated with Pd(PPh₃)₄ (0.025 g, 0.021mmol), sparged again with Ar and heated at 80° C. overnight. The mixturewas cooled to RT, treated with satd. NaHCO₃, extracted with EtOAc (2×)and the combined organics were washed with brine, dried over MgSO₄,concentrated to dryness and purified via silica gel chromatography(MeOH/DCM) to affordN-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(160 mg, 75%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 13.05 (s,1H), 10.91 (d, J=2.7 Hz, 1H), 8.40 (1H, d, J=8.1 Hz, 1H), 8.36 (d, J=5.7Hz, 1H), 8.33 (s, 1H), 8.04 (s, 1H), 7.57 (d, J=11.2 Hz, 1H), 7.30 (d,J=2.5 Hz, 1H), 6.61 (dd, J=5.7, 2.5 Hz, 1H), 3.94-3.77 (m, 5H), 3.47 (t,J=8.2 Hz, 2H), 3.37 (t, J=11.8 Hz, 2H), 1.75-1.64 (m, 2H), 1.59 (m, 2H);MS (ESI) m/z: 501.1 (M+H+).

Example 95

A suspension of 3-fluoro-4-aminophenol (8.0 g, 63.0 mmol) indimethylacetamide (80 mL) was de-gassed in vacuo and treated withpotassium tert-butoxide (7.3 g, 65 mmol). The resultant mixture wasstirred at RT for 30 min. 2,4-Dichloropyridine (8 g, 54 mmol) was addedand the mixture was heated to 80° C. for 12 h. The solvent was removedunder reduced pressure to give a residue which was partitioned betweenwater and EtOAc (3×). The organic layers were washed with satd. brine,dried over MgSO₄, concentrated in vacuo and purified by silica gelcolumn chromatography to give4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (11 g, 86% yield). ¹HNMR (300 MHz, DMSO-d₆): δ 8.24 (d, J=5.7 Hz, 1H), 7.00 (dd, J=9.0, 2.7Hz, 1H), 6.89-6.73 (m, 4H), 5.21 (br s, 2H); MS (ESI) m/z: 239.2 (M+H+).

A solution of 4-(2-chloropyridin-4-yloxy)-2-fluorobenzenamine (3 g, 12.6mmol),1-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole(5.2 g, 25.2 mmol), and Na₂CO₃ (2.7 g, 25.2 mmol) in DME (18 mL)/water(6 mL) was sparged with nitrogen for 20 min. Pd(PPh₃)₄ (729 mg, 0.63mmol) was added and the resulting mixture was heated to 100° C. for 16h. The solvent was removed under reduced pressure and the crude productwas suspended in water and extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄, concentrated in vacuo and purifiedvia silica gel chromatography to give2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (2 g,56% yield). ¹H NMR (300 MHz, DMSO-d₆): δ 8.31 (d, J=5.7 Hz, 1H), 8.21(s, 1H), 7.92 (s, 1H), 7.12 (d, J=2.4 Hz, 1H), 6.96 (m, 1H), 6.85-6.72(m, 2H), 6.56 (m, 1H), 5.15 (s, 2H), 3.84 (s, 3H); MS (ESI) m/z: 285.0(M+H⁺).

A mixture of2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150g, 0.528 mmol) and TEA (3.2 mL, 22.93 mmol) in DCM (5 mL) was cooled to0° C., treated with a solution of Example B2 (0.164 g, 0.705 mmol) inDCM (1.5 mL), warmed to RT and stirred for 1 h. The mixture was treatedwith water, stirred for 10 min, the layers separated and the organiclayer dried over Na₂SO₄, concentrated to dryness and purified via silicagel chromatography (MeOH/DCM). The material was treated with Et2O,sonicated and the resulting solid collected via filtration to affordN-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(167 mg, 66%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.74 (d, J=2.5 Hz, 1H),8.36 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.19 (t, J=9.1 Hz, 1H), 7.95 (d,J=0.7 Hz, 1H), 7.28 (dd, J=11.7, 2.7 Hz, 1H), 7.22 (d, J=2.4 Hz, 1H),7.03 (dd, J=9.1, 2.5 Hz, 1H), 6.67 (dd, J=5.7, 2.4 Hz, 1H), 3.93-3.77(m, 8H), 3.46 (t, J=8.2 Hz, 2H), 3.38 (dd, J=12.5, 10.6 Hz, 2H), 1.71(qd, J=12.2, 4.5 Hz, 2H), 1.60-1.57 (m, 2H); MS (ESI) m/z: 481.2 (M+H⁺).

Example 96

KOtBu (1.016 g, 9.05 mmol) was added to a solution of4-amino-2-chlorophenol (1.00 g, 6.97 mmol) in DMF (35 mL) at RT andstirred 45 min. 2,4-Dichloropyridine (1.340 g, 9.05 mmol) was then addedand the reaction was heated at 90° C. overnight. The mixture was cooledto RT, diluted with H₂O and EtOAc, the layers separated and the aqueouslayer was extracted with EtOAc (3×). The combined organics were washedwith H₂O (1×), then brine (2×), dried over MgSO₄, concentrated in vacuoand purified by silica gel chromatography (EtOAc/Hex) to afford3-chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 50%) as a waxyyellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ 8.24 (d, J=5.7 Hz, 1H), 7.02(d, J=8.7 Hz, 1H), 6.87-6.82 (m, 2H), 6.73-6.72 (m, 1H), 6.58-6.56 (m,1H), 5.50 (br s, 2H); MS (ESI) m/z: 254.9 (M+H⁺); 256.9 (M+2+H⁺).

3-Chloro-4-(2-chloropyridin-4-yloxy)benzenamine (0.89 g, 3.49 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole (0.871g, 4.19 mmol) and K₂CO₃ (1.302 g, 9.42 mmol) were combined in DME (6mL)/H₂O (7.5 mL) and the headspace was flushed with Ar for 10 min.Pd(Ph₃P)₄ (0.202 g, 0.174 mmol) was then added and the biphasic reactionwas heated at 90° C. overnight. The mixture was cooled to RT andfiltered to remove insoluble material. The filtrate was diluted withTHF, washed with brine (3×) and the combined aqueous phases wereback-extracted with THF (2×). The combined organics were washed withbrine (1×), dried over MgSO₄, concentrated in vacuo and purified bysilica gel chromatography (MeOH/CHCl₃) to afford3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (1.10g, 83%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.30-8.29 (m, 1H), 8.22 (s, 1H),7.92 (s, 1H), 7.12 (m, 1H), 7.00-6.98 (m, 1H), 6.72 (br s, 1H),6.58-6.54 (m, 1H), 6.47-6.44 (m, 1H), 5.44 (s, 2H), 3.84 (s, 3H); MS(ESI) m/z: 301.1 (M+H⁺): 303.0 (M+2+H⁺).

A 0° C. mixture of3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150g, 0.499 mmol) and TEA (0.1 mL, 0.716 mmol) in DCM (5 mL) was treatedwith a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL),warmed to RT and stirred for 1 h. The mixture was treated with water,stirred for 10 min, the layers separated and the organic layer driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to affordN-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(176 mg, 71%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.57 (s, 1H), 8.34 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 7.96 (s, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.46(dd, J=8.8, 2.6 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H),6.55 (dd, J=5.7, 2.5 Hz, 1H), 3.94-3.76 (m, 8H), 3.46 (t, J=8.2 Hz, 2H),3.37 (t, J=11.7 Hz, 2H), 1.76-1.66 (m, 2H), 1.59 (d, J=12.4 Hz, 2H); MS(ESI) m/z: 497.2 (M+H⁺).

Example 97

A mixture of Example C8 (0.243 g, 0.518 mmol), acetamide (0.184 g, 3.11mmol), Cs₂CO₃ (0.422 g, 1.294 mmol) and Xantphos (0.090 g, 0.155 mmol)in dioxane (3 mL) was sparged with Ar, treated with Pd₂(dba)₃ (0.062 g,0.067 mmol), sparged again with Ar and heated at 100° C. overnight. Themixture was cooled to RT, treated with brine, extracted with EtOAc (3×)and the combined organics were dried over Na₂SO₄, concentrated todryness and purified twice via silica gel chromatography (MeOH/DCM, thenMeOH/EtOAc) to affordN-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(74 mg, 29%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (d, J=2.7 Hz, 1H),10.57 (s, 1H), 8.39 (d, J=8.1 Hz, 1H), 8.17 (d, J=5.7 Hz, 1H), 7.61 (d,J=2.4 Hz, 1H), 7.58 (d, J=11.2 Hz, 1H), 6.64 (dd, J=5.7, 2.4 Hz, 1H),3.93-3.83 (m, 3H), 3.81 (m, 2H), 3.48 (t, J=8.2 Hz, 2H), 3.37 (dd,J=12.4, 10.6 Hz, 2H), 2.03 (s, 3H), 1.71 (qd, J=12.2, 4.5 Hz, 2H),1.62-1.56 (m, 2H); MS (ESI) m/z: 492.1 (M+H⁺).

Example 98

A 0° C. solution of Example A20 (0.170 g, 0.562 mmol) and TEA (0.1 mL,0.716 mmol) in DCM (5 mL) was treated with a solution of Example B4(0.165 g, 0.799 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h.The mixture was treated with water, stirred for 10 min, the layersseparated and the organic layer dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM). Thematerial was treated with Et2O, sonicated and the resulting solidcollected via filtration to affordN-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide(170 mg, 64%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.37 (d,J=5.7 Hz, 1H), 8.26 (s, 1H), 8.20 (dd, J=12.5, 7.4 Hz, 1H), 7.97 (s,1H), 7.57 (dd, J=11.2, 7.4 Hz, 1H), 7.23 (d, J=2.5 Hz, 1H), 6.71 (dd,J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 3.83-3.78 (m, 2H), 3.50-3.46 (m, 4H),3.40-3.37 (m, 2H), 3.26 (s, 3H); MS (ESI) m/z: 473.1 (M+H⁺).

Example 99

A 0° C. solution of phosgene (20% in toluene, 0.711 mL, 0.980 mmol) inDCM (6 mL) was treated slowly drop-wise with a solution of Example B9(0.129 g, 0.700 mmol) and pyridine (0.113 mL, 1.400 mmol) in DCM (2 mL)warmed to RT, and stirred for 0.5 h. The mixture was concentrated todryness, dissolved in DCM (2 mL), added to a 0° C. solution of ExampleA22 (0.069 g, 0.218 mmol) and TEA (0.091 mL, 0.654 mmol) in DCM (1 mL),warmed to RT and stirred overnight. The mixture was diluted withadditional DCM, washed with water (3×), dried over MgSO₄, concentratedto dryness and purified via reverse-phase chromatography (MeCN/H₂O with0.1% TFA). The organic were removed under reduced pressure and theaqueous residue was treated with satd. NaHCO₃, extracted with EtOAc (3×)and the combined organics dried over MgSO₄ and concentrated to drynessto affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-(1-methoxycyclopropyl)ethyl)-2-oxoimidazolidine-1-carboxamide(69 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (d, J=2.7 Hz, 1H), 8.41(d, J=8.1 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.97 (d, J=0.7Hz, 1H), 7.57 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.64 (dd,J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 3.81-3.79 (m, 2H), 3.51 (t, J=8.3 Hz,2H), 3.34 (t, J=7.5 Hz, 2H), 3.16 (s, 3H), 1.77 (t, J=7.4 Hz, 2H),0.67-0.66 (m, 2H), 0.42-0.41 (m, 2H); MS (ESI) m/z: 529.2 (M+H⁺).

Example 100

A 0° C. solution of Example A22 (0.170 g, 0.533 mmol) and TEA (0.1 mL,0.716 mmol) in DCM (5 mL) was treated with a solution of Example B4(0.165 g, 0.799 mmol) in DCM (1.5 mL), warmed to RT and stirred for 1 h.The mixture was treated with water, stirred for 10 min, the layersseparated and the organic layer dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM). Thematerial was treated with Et₂O, sonicated and the resulting solidcollected via filtration to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide(152 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.88 (d, J=2.7 Hz, 1H),8.40 (d, J=8.1 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98 (s,1H), 7.58 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7,2.5 Hz, 1H), 3.84 (s, 3H), 3.82-3.80 (m, 2H), 3.51-3.49 (m, 4H),3.40-3.37 (m, 2H), 3.26 (s, 3H); MS (ESI) m/z: 489.1 (M+H⁺).

Example 101

A mixture of Example C8 (0.200 g, 0.426 mmol), N,N-dimethyl urea (0.225g, 2.56 mmol), Cs₂CO₃ (0.347 g, 1.065 mmol) and Xantphos (0.074 g, 0.128mmol) in dioxane (3 mL) was sparged with Ar, treated Pd₂(dba)₃ (0.051 g,0.055 mmol), sparged again with Ar and heated at 100° C. overnight. Themixture was cooled to RT, treated with brine, extracted with EtOAc (3×)and the combined organics were dried over Na₂SO₄, concentrated todryness and purified twice via silica gel chromatography (MeOH/DCM, thenMeOH/EtOAc). The material was suspended in 1:1 EtOAc/Et₂O, sonicated andthe resulting solid collected via filtration to affordN-(5-chloro-4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(98 mg, 44%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (d, J=2.7 Hz, 1H), 8.91(s, 1H), 8.39 (d, J=8.0 Hz, 1H), 8.10 (d, J=5.7 Hz, 1H), 7.56 (d, J=11.2Hz, 1H), 7.34 (d, J=2.4 Hz, 1H), 6.56 (dd, J=5.7, 2.4 Hz, 1H), 3.93-3.86(m, 3H), 3.83-3.81 (m, 2H), 3.47 (m, 2H), 3.37 (m, 2H), 2.87 (s, 6H),1.71 (m, 2H), 1.59 (m, 2H); MS (ESI) m/z: 521.2 (M+H⁺).

Example 102

Using a procedure analogous to Example 95, 2-fluoro-4-aminophenol (2.6g, 24 mmol) and 2,4-dichloropyridine (2.88 g, 20 mol) were combined toprovide 4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3.2 g, 67%). ¹H NMR(400 MHz, DMSO-d₆): δ 8.25 (d, J=5.6 Hz, 1H), 6.99 (m, 1H), 6.90 (m,2H), 6.50 (d, J=1.6 Hz, 1H), 6.41 (d, J=10.4 Hz, 1H), 5.51 (s, 2H); MS(ESI) m/z: 239.1 (M+H⁺).

Using a procedure analogous to Example 95,4-(2-chloropyridin-4-yloxy)-3-fluoroaniline (3 g, 11.6 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(3.4 g, 16.4 mmol), Na₂CO₃ (2.7 g, 25.2 mmol) and Pd(Ph₃)₄ (1.5 g, 0.1eq) were combined to give3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (1.1g, 34%). ¹H NMR (400 MHz, DMSO-d₆): δ (8.31 (d, J=5.6 Hz, 1H), 8.22 (s,1H), 7.93 (s, 1H), 7.14 (s, 1H), 6.98 (m, 1H), 6.55-6.49 (m, 2H), 6.42(d, J=7.2 Hz, 1H), 5.44 (s, 2H), 3.86 (s, 3H); MS (ESI) m/z: (M+H⁺):285.2.

A 0° C. mixture of3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline (0.150g, 0.528 mmol) and TEA (0.1 mL, 0.716 mmol) in DCM (5 mL) was treatedwith a solution of Example B2 (0.164 g, 0.705 mmol) in DCM (1.5 mL),warmed to RT and stirred for 1 h. The mixture was treated with water,stirred for 10 min, the layers separated and the organic layer driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM). The material was treated with DCM, sonicatedand allowed to evaporate overnight. The residue was treated with Et₂O,sonicated and the resulting solid collected via filtration to affordN-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(154 mg, 61%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.59 (s, 1H), 8.35 (d,J=5.7 Hz, 1H), 8.25 (s, 1H), 7.95 (s, 1H), 7.74 (dd, J=12.9, 2.2 Hz,1H), 7.36-7.28 (m, 2H), 7.22 (d, J=2.5 Hz, 1H), 6.62 (dd, J=5.7, 2.5 Hz,1H), 3.94-3.82 (m, 6H), 3.79 (m, 2H), 3.45 (m, 2H), 3.37 (m, 2H), 1.72(m, 2H), 1.59 (m, 2H); MS (ESI) m/z: (M+H⁺): 481.2.

Example 103

A solution of Example B5 (0.071 g, 0.452 mmol) and pyridine (0.114 mL,1.412 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.698g, 1.412 mmol), stirred for 15 min, then concentrated to dryness. Theresidue was dissolved in DCM (2 mL), treated with a solution of ExampleA22 (0.09 g, 0.282 mmol) and TEA (0.118 mL, 0.847 mmol) in DCM (2 mL)and stirred at RT for 1 h. The mixture was diluted with water, extractedwith DCM (2×) and the combined organics were washed with brine, driedover Na₂SO₄ and concentrated to dryness. The material was treated with60% EtOAc/Hex, sonicated and the resulting solid collected viafiltration to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxypropyl)-2-oxoimidazolidine-1-carboxamide(109 mg, 77%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (d, J=2.7 Hz, 1H),8.41 (d, J=8.1 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98 (s,1H), 7.57 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7,2.5 Hz, 1H), 3.84 (s, 3H), 3.82-3.80 (m, 2H), 3.47 (m, 2H), 3.34 (m,2H), 3.27 (m, 2H), 3.22 (s, 3H), 1.73 (m, 2H); MS (ESI) m/z: (M+H⁺):503.2.

Example 104

A 0° C. solution of phosgene (20% in toluene, 0.853 mL, 1.177 mmol) inDCM (6 mL) was treated slowly drop-wise with a solution of Example B10(0.119 g, 0.841 mmol) and pyridine (0.136 mL, 1.681 mmol) in DCM (2 mL),warmed to RT, stirred for 0.5 h, then concentrated to dryness. Theresidue was dissolved in DCM (2 mL), added to a 0° C. solution ofExample A22 (0.084 g, 0.263 mmol) and TEA (0.110 mL, 0.788 mmol) in DCM(1 mL), warmed to RT and stirred overnight. The mixture was diluted withDCM, washed with water (3×), dried over MgSO₄, concentrated to drynessand purified via silica gel chromatography (MeOH/DCM) to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide(44 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.77 (d, J=2.7 Hz, 1H), 8.39(d, J=8.1 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H),7.57 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7, 2.5Hz, 1H), 5.03 (m, 1H), 4.77 (t, J=6.7 Hz, 2H), 4.68 (t, J=7.3 Hz, 2H),3.89-3.83 (m, 5H), 3.77 (m, 2H); MS (ESI) m/z: (M+H⁺): 487.1.

Example 105

A solution of Example B8 (298 mg, 0.941 mmol) and pyridine (112 mg,1.412 mmol) in DCM (4 mL) was added to phosgene (20% in toluene, 1.164g, 2.353 mmol), under Ar, stirred for 15 minutes, then concentrated todryness. The residue was treated with a solution of Example A22 (150 mg,0.471 mmol) and TEA (238 mg, 2.353 mmol) in DCM (4 mL) and stirred at RTovernight. The mixture was treated with water, extracted with EtOAc (2×)and the combined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via reverse-phase chromatography(MeCN/H₂O with 0.1% TFA). The organics were removed under reducedpressure and the resulting aqueous residue was treated with satd.NaHCO₃, extracted with EtOAc (2×) and the combined organics were washedwith brine, dried over Na₂SO₄ and concentrated to dryness. The materialwas further purified via silica gel chromatography (MeOH/EtOAc) toafford(S)—N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(1-methoxypropan-2-yl)-2-oxoimidazolidine-1-carboxamide(36 mg, 15%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (d, J=2.6 Hz, 1H), 8.40(d, J=8.0 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s, 1H),7.56 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 6.64 (dd, J=5.7, 2.5Hz, 1H), 4.10-4.08 (m, 1H), 3.84 (s, 3H), 3.80 (m, 2H), 3.51-3.31 (m,4H), 3.25 (s, 3H), 1.09 (d, J=6.9 Hz, 3H); MS (ESI) m/z: (M+H⁺): 503.1.

Example 106

A solution of Example B11 (0.103 g, 0.393 mmol) in DCM (4 mL) wastreated with a solution of Example A22 (0.125 g, 0.393 mmol) and TEA(0.082 mL, 0.590 mmol) in DCM (4 mL), stirred at RT for 1 h, dilutedwith DCM, washed with water (2×), then brine (1×), dried over MgSO₄ andconcentrated to dryness. The material was purified via silica gelchromatography (MeOH/EtOAc/Hex) to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide(100 mg, 47%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.80 (d, J=2.7 Hz, 1H),8.40-8.35 (m, 2H), 8.27 (s, 1H), 7.98 (s, 1H), 7.58 (d, J=11.3 Hz, 1H),7.21 (d, J=2.4 Hz, 1H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 4.25 (t, J=5.1 Hz,2H), 3.86-3.80 (m, 5H), 3.59-3.50 (m, 4H); MS (ESI) m/z: (M+H⁺): 543.1.

Example 107

A solution of Example B7 (0.076 g, 0.452 mmol) and pyridine (0.114 mL,1.412 mmol) in DCM (2 mL) was added to phosgene (20% in toluene, 0.698g, 1.412 mmol), under Ar, stirred for 15 min, then concentrated todryness. The residue was dissolved in DCM (2 mL), treated with asolution of Example A22 (0.09 g, 0.282 mmol) and TEA (0.118 mL, 0.847mmol) in DCM (2 mL) and stirred at RT for 1 h. The mixture was treatedwith water, extracted with DCM (2×) and the combined organics werewashed with brine, dried over Na₂SO₄ and concentrated to dryness. Thematerial was treated with 50% EtOAc/Hex, sonicated and the resultingsolid collected via filtration to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclohexyl-2-oxoimidazolidine-1-carboxamide(125 mg, 86%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (d, J=2.7 Hz, 1H),8.40 (d, J=8.1 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.27 (s, 1H), 7.98 (s,1H), 7.58 (d, J=11.2 Hz, 1H), 7.21 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7,2.4 Hz, 1H), 3.84 (s, 3H), 3.81-3.78 (m, 2H), 3.63-3.60 (m, 1H),3.46-3.44 (m, 2H), 1.71-1.67 (m, 5H), 1.37-1.35 (m, 4H), 1.10-1.07 (m,1H); MS (ESI) m/z: (M+H⁺): 513.2.

Example 108

A 0° C. solution of Example C9 (0.350 g, 0.812 mmol) in DMF (5 mL) wastreated with NaH (60% in mineral oil, 0.100 g, 2.50 mmol), stirred at RTfor 0.5 h, treated with Example C4 (0.500 g, 1.836 mmol) and stirred atRT overnight. The mixture was treated with water, extracted with EtOAc(3×) and the combined organics were dried over Na₂SO₄, concentrated todryness and purified via silica gel chromatography (MeOH/DCM) to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxy-3-methylbutyl)-2-oxoimidazolidine-1-carboxamide(128 mg, 28%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s, 1H), 8.38 (m, 2H),8.26 (s, 1H), 7.97 (d, J=0.7 Hz, 1H), 7.57 (d, J=11.3 Hz, 1H), 7.20 (d,J=2.5 Hz, 1H), 6.64 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (s, 3H), 3.80 (m, 2H),3.48 (t, J=8.2 Hz, 2H), 3.28 (m, 2H), 3.09 (s, 3H), 1.70 (m, 2H), 1.11(s, 6H); MS (ESI) m/z: (M+H⁺): 531.2.

Example 109

A 0° C. mixture of 2-chloro-4-hydroxypyridine (817 mg, 6.30 mmol) in DMF(30 mL) was treated with NaH (60% in mineral oil, 277 mg, 6.93 mmol),stirred for 1 h, treated with 5-bromo-2,4-difluoronitrobenzene (1.50 g,6.30 mmol) and heated at 90° C. overnight. The mixture was cooled to RT,diluted with water, extracted with EtOAc (2×) and the combined organicswere washed with brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography (EtOAc/Hex) to afford4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16 g, 53%). MS(ESI) m/z: (M+H⁺): 348.9.

A mixture of 4-(2-bromo-5-fluoro-4-nitrophenoxy)-2-chloropyridine (1.16g, 3.34 mmol) and Raney Ni (0.5 g) in EtOH (40 mL) was hydrogenated (1atm) overnight, the solids removed via filtration and washed with EtOH.The filtrate was concentrated to dryness, the residue dissolved inEtOAc, washed with brine, dried over Na₂SO₄ and concentrated to drynessto afford 5-bromo-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline (994 mg,94%). MS (ESI) m/z: (M+H⁺): 318.9.

A mixture of 5-bromo-4-((2-chloropyridin-4-yl)oxy)-2-fluoroaniline (994mg, 3.13 mmol), K₃PO₄ (1.993 g, 9.39 mmol) and1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(716 mg, 3.44 mmol) in DMF (10 mL) and water (1.5 mL) was sparged withAr, treated with Pd(PPh₃)₄ (362 mg, 0.313 mmol) and heated at 90° C.overnight. The mixture was cooled to RT, diluted with water, extractedwith EtOAc (2×) and the combined organics were washed with brine, driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc/Hex) to afford5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline(594 mg, 52%). MS (ESI) m/z: (M+H⁺): 363.0.

A solution of Example B1 (141 mg, 0.826 mmol) and pyridine (98 mg, 1.239mmol) in DCM (4 mL) was added to phosgene (20% in toluene, 1.021 g,2.065 mmol), under Ar, stirred for 15 minutes, then concentrated todryness. The residue was treated with a solution of5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline(150 mg, 0.413 mmol) and TEA (209 mg, 2.065 mmol) in DCM (4 mL) andstirred at RT for 0.5 h. The mixture was diluted with water, extractedwith EtOAc (2×) and combined organics were washed with brine, dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/EtOAc) to affordN-(5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(134 mg, 58%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (d, J=2.7 Hz, 1H),8.54 (d, J=8.2 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s,1H), 7.55 (d, J=11.3 Hz, 1H), 7.19 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7,2.5 Hz, 1H), 3.93-3.87 (m, 3H), 3.84 (s, 3H), 3.83-3.78 (m, 2H), 3.47(m, 2H), 3.37 (m, 2H), 1.71 (m, 2H), 1.59 (m, 2H); MS (ESI) m/z: (M+H⁺):559.1.

Example 110

A 0° C. solution of phosgene (20% in toluene, 1.50 mL, 2.84 mmol) wastreated with a solution of Example B12 (0.200 g, 0.979 mmol) andpyridine (0.150 g, 1.896 mmol) in DCM (10 mL), stirred at RT for 0.5 h,then concentrated to dryness. The residue was treated with a solution ofExample A22 (0.150 g, 0.471 mmol) and pyridine (0.150 g, 1.896 mmol) inDCM (10 mL) and stirred at RT for 2 h. The mixture was concentrated todryness and purified via silica gel chromatography (EtOAc/DCM) to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4,4-difluorocyclohexyl)-2-oxoimidazolidine-1-carboxamide(63 mg, 24%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.91 (d, J=2.7 Hz, 1H), 8.37(m, 2H), 8.26 (s, 1H), 7.97 (s, 1H), 7.57 (d, J=11.2 Hz, 1H), 7.20 (d,J=2.5 Hz, 1H), 6.64 (dd, J=5.7, 2.5 Hz, 1H), 3.84 (m, 6H), 3.46 (t,J=8.2 Hz, 2H), 2.06-1.97 (m, 4H), 1.68 (m, 4H); MS (ESI) m/z: (M+H⁺):549.2.

Example 111

A 0° C. solution of Example B14 (0.159 g, 1.031 mmol) and pyridine(0.272 mL, 3.37 mmol) in DCM (5 mL) was treated drop-wise with phosgene(20% in toluene, 1.579 mL, 2.99 mmol), warmed to RT, added to a solutionof Example A22 (0.179 g, 0.561 mmol) and TEA (0.235 mL, 1.684 mmol) inDCM (5 mL) and stirred at RT for 2 h. The mixture was treated with satd.NaHCO₃, extracted with DCM (3×) and the combined organics were driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM) to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclopentyl-2-oxoimidazolidine-1-carboxamide(137 mg, 49%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.93 (d, J=2.7 Hz, 1H),8.40 (d, J=8.0 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s,1H), 7.57 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.4 Hz, 1H), 6.64 (dd, J=5.7,2.5 Hz, 1H), 4.19 (m, 1H), 3.84 (s, 3H), 3.81-3.79 (m, 2H), 3.46 (m,2H), 1.77-1.75 (m, 2H), 1.69-1.50 (m, 6H); MS (ESI) m/z: (M+H⁺): 499.2.

Example 112

A 0° C. solution of Example C9 (0.30 g, 0.696 mmol) in DMF (3 mL) wastreated with NaH (60% in mineral oil, 0.070 g, 1.741 mmol), stirred atRT for 0.5 h, treated drop-wise with 2-(tert-butyl)oxirane (0.139 g,1.393 mmol), stirred at RT for 1 h, then heated at 60° C. overnight.Additional 2-(tert-butyl)oxirane (0.1 mL) was added, the mixture heatedat 60° C. for 7 h, cooled to RT, treated with additional NaH (60% inmineral oil, 0.070 g, 1.741 mmol), stirred for 20 min, treated with-(tert-butyl)oxirane (0.139 g, 1.393 mmol) and heat4ed at 60° C.overnight. The mixture was cooled to RT, treated with water, extractedwith EtOAc (3×) and the combined organics were washed with brine, driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (EtOAc, MeOH/DCM) to affordN-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide(29 mg, 7.5%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.95 (d, J=2.7 Hz, 1H),8.41 (d, J=8.1 Hz, 1H), 8.36 (d, J=5.7 Hz, 1H), 8.26 (s, 1H), 7.97 (s,1H), 7.57 (d, J=11.3 Hz, 1H), 7.20 (d, J=2.5 Hz, 1H), 6.64 (dd, J=5.7,2.5 Hz, 1H), 4.84 (d, J=5.5 Hz, 1H), 3.84 (s, 3H), 3.80 (m, 2H), 3.58(m, 2H), 3.31 (m, 2H), 3.05 (m, 1H), 0.87 (s, 9H); MS (ESI) m/z: (M+H⁺):531.2.

Example 113

A solution of 2-chloro-1,3-difluoro-4-nitrobenzene (80 g, 415 mmol) andbenzyl alcohol (47 g, 435 mmol) in DMF (500 mL) was treated with K₂CO₃(120 g, 870 mmol) and stirred at RT overnight. The mixture was pouredinto water, extracted with EtOAc (3×) and the combined organics werewashed with brine, dried over Na₂SO₄, concentrated to dryness andpurified via silica gel chromatography to afford1-(benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene (45 g, 39%). ¹H NMR (400MHz, DMSO-d₆): δ 8.21 (t, J=9.2 Hz, 1H), 7.49-730 (m, 6H), 5.40 (s, 2H).

A 0° C. solution of 1-(benzyloxy)-2-chloro-3-fluoro-4-nitrobenzene (45g, 160 mmol) in DCM (200 mL) was treated drop-wise with tribromoborane(7.9 g, 320 mmol) over 0.5 h, stirred at 0° C. for 2 h, treated withsatd. NaHCO₃ and was washed with brine. The organic layer was dried overNa₂SO₄ and concentrated to afford 2-chloro-3-fluoro-4-nitrophenol (25 g,82%). ¹H NMR (400 MHz, DMSO-d₆): δ 9.39 (s, 1H), 6.95 (m, 2H), 4.67(brs, 2H).

A 0° C. solution of 2-chloro-3-fluoro-4-nitrophenol (25 g, 130.9 mmol)in 1:1 MeOH and THF (400 mL) was treated with NH₄Cl (70 g, 1.3 mol),followed by the portion-wise addition of zinc (83.2 g, 1.3 mol), thenwarmed to RT and stirred for 2 h. The solids were removed viafiltration, the filtrate concentrated to dryness and the residue wasdissolved in EtOAc, washed with brine, dried over Na₂SO₄ andconcentrated to afford 4-amino-2-chloro-3-fluorophenol (16 g, 76%).¹H-NMR (400 MHz, DMSO-d₆): δ 9.41 (s, 1H), 6.59-6.51 (m, 2H), 4.65 (s,2H); MS (ESI): m/z 162.2 [M+H]⁺.

A mixture of 4-amino-2-chloro-3-fluorophenol (11 g, 68.3 mmol) andpotassium 2-methylpropan-2-olate (8.4 g, 75.2 mmol) in DMA (120 mL) wasstirred at RT under N₂ for 0.5 h, treated with 2,4-dichloropyridine (9.1g, 62.1 mmol), and heated at 80° C. for 8 h. The mixture wasconcentrated to dryness, the residue treated with water, extracted withEtOAc (3×) and the combined organics were washed with brine, dried overNa₂SO₄, concentrated to dryness and purified via silica gelchromatography to afford3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10 g, 59%). ¹H NMR(400 MHz, DMSO-d₆): δ 8.26 (d, J=5.6 Hz, 1H), 6.98-6.96 (m, 2H), 6.88(dd, J=5.6 Hz, 2.0 Hz, 1H), 6.80 (t, J=9.2 Hz, 1H), 5.57 (s, 2H).

A solution of 3-chloro-4-(2-chloropyridin-4-yloxy)-2-fluoroaniline (10g, 36.8 mmol) in DMF (140 mL) and water (30 mL) was treated with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(8.4 g, 40.5 mmol), K₃PO₄ (14.9 g, 73.6 mmol) and Pd(PPh₃)₄ (4.3 g, 3.7mmol), sparged with N₂ and heated at 80° C. for 12 h. The mixture wascooled to RT, poured into water and extracted with EtOAc (3×). Thecombined organics were washed with brine, dried over Na₂SO₄,concentrated to dryness and purified via silica gel chromatography toafford3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline(3.0 g, 26%). ¹H NMR (400 MHz, DMSO-d₆): δ 8.32 (d, J=6.0 Hz, 1H), 8.24(s, 1H), 7.95 (s, 1H), 7.15 (d, J=1.6 Hz, 1H), 6.94 (d, J=8.8 Hz, 1H),6.80 (t, J=8.8 Hz, 1H), 6.54-6.52 (m, 1H), 5.51 (s, 2H), 3.85 (s, 3H);MS (ESI): m/z 318.2 (M+H⁺).

A mixture of3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)aniline(0.250 g, 0.784 mmol) and TEA (0.150 mL, 1.076 mmol) in DCM (5 mL) wastreated drop-wise with a solution of Example B2 (0.219 g, 0.941 mmol) inDCM (5 mL), warmed to RT and stirred overnight. The mixture was treatedwith water, extracted with DCM (3×) and the combined organics were driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM). The material was treated with MeCN, sonicatedand the resulting solid collected via filtration to affordN-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(242 mg, 60%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.86 (s, 1H), 8.36 (d,J=5.7 Hz, 1H), 8.26 (s, 1H), 8.18 (t, J=8.9 Hz, 1H), 7.97 (s, 1H),7.25-7.20 (m, 2H), 6.65 (dd, J=5.7, 2.4 Hz, 1H), 3.90 (m, 3H), 3.84 (s,3H), 3.81 (m, 2H), 3.47 (m, 2H), 3.38 (m, 2H), 1.77-1.65 (m, 2H), 1.59(m, 2H); MS (ESI) m/z: (M+H⁺): 515.1.

Example 114

A mixture of Example C8 (1 g, 2.131 mmol), t-butyl carbamate (0.749 g,6.39 mmol), Cs₂CO₃ (2.083 g, 6.39 mmol) and Xantphos (0.555 g, 0.959mmol) in dioxane (15 mL) was sparged with Ar, treated with Pd₂(dba)₃(0.293 g, 0.320 mmol), sparged again with Ar and heated at 100° C.overnight. The mixture was cooled to RT, treated with satd. NaHCO₃,extracted with EtOAc (3×) and the combined organics were dried overNa₂SO₄, passed through a pad of silica gel and concentrated to drynessto afford crude tert-butyl(4-(2-chloro-5-fluoro-4-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamido)phenoxy)pyridin-2-yl)carbamate(1.32 g, 113%) which was used without further purification. MS (ESI)m/z: (M+H⁺): 550.1.

tert-Butyl(4-(2-chloro-5-fluoro-4-(2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamido)phenoxy)pyridin-2-yl)carbamate(1.32 g, 2.400 mmol) was combined with TFA (20 mL), stirred at RTovernight and concentrated to dryness. The residue was treated with DCM,sonicated, the solid removed via filtration and the filtrateconcentrated to dryness and purified via silica gel chromatography(MeOH/EtOAc) to affordN-(4-((2-aminopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(382 mg, 35%). MS (ESI) m/z: (M+H⁺): 450.1.

A RT solution of cyanoacetic acid (0.500 g, 5.88 mmol) in DCM (20 mL)and DMF (0.1 mL) was treated drop-wise with oxalyl chloride (1.1 mL,12.52 mmol), stirred at RT for 2.5 h, then concentrated to dryness. Theresidue was dissolved in DCM (5 mL), added drop-wise to a 0° C. solutionofN-(4-((2-aminopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(0.210 g, 0.467 mmol) in pyridine (10 mL), stirred for 0.5 h, thenconcentrated to dryness. The residue was dissolved in DCM, washed withsatd. NaHCO₃ and the aqueous layer extracted with EtOAc (3×). Thecombined organics were dried over Na₂SO₄, concentrated to dryness andpurified twice via silica gel chromatography (MeOH/DCM, thenMeOH/EtOAc). The material was further purified via silica gelchromatography (MeOH/DCM) to affordN-(5-chloro-4-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(120 mg, 49%). MS (ESI) m/z: (M+H⁺): 516.8.

Example 115

A 0° C. solution of phosgene (15% in toluene, 2 mL, 2.84 mmol) in DCM (5mL) was treated drop-wise with a solution of pyridine (0.1 mL, 1.24mmol) and Example B18 (0.095 g, 0.82 mmol) in DCM (5 mL), warmed to RT,stirred for 1 h, then concentrated to dryness. The residue was dissolvedin DCM (5 mL), cooled to 0° C., treated with a solution of Example A23(0.10 g, 0.409 mmol) and pyridine (0.1 mL) in DCM (5 mL), warmed to RTand stirred overnight. The mixture was treated with satd. NaHCO₃,extracted with EtOAc (3×) and the combined organics were dried overNa₂SO₄ and concentrated to dryness. The resultant material was treatedwith EtOAc and sonicated. The resulting solid was collected byfiltration to afford4-((6-(3-ethyl-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide(105 mg, 66%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.02 (s, 1H), 8.79 (q,J=4.8 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.27 (d, J=2.9 Hz, 1H), 8.10 (d,J=9.0 Hz, 1H), 7.77 (dd, J=9.0, 2.9 Hz, 1H), 7.41 (d, J=2.6 Hz, 1H),7.18 (dd, J=5.6, 2.7 Hz, 1H), 3.81 (m, 2H), 3.47 (m, 2H), 3.26 (q, J=7.2Hz, 2H), 2.78 (d, J=4.8 Hz, 3H), 1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z:385.2 (M+H⁺).

Example 116

A 0° C. solution of phosgene (15% in toluene, 3 mL, 4.21 mmol) in DCM(10 mL) was treated drop-wise with a solution of pyridine (0.350 mL,4.35 mmol) and Example B3 (0.601 g, 4.17 mmol) in DCM (4 mL), stirredfor 30 min, then concentrated to dryness. The residue was dissolved inDCM (4 mL) and added drop-wise to a 0° C. solution of Example A24 (0.95g, 3.48 mmol) and pyridine (0.35 mL, 4.35 mmol) in DCM (20 mL). After˜15 min of stirring, the reaction mixture was concentrated to drynessand left under high vacuum overnight. The product was dissolved in DCMand extracted with satd aq NaHCO₃. The aqueous layer was back-extractedwith DCM (3×). The organic phases were combined, dried (Na₂SO₄) andconcentrated to dryness to afford a red solid. The solid was purifiedvia silica gel chromatography (1-6% MeOH/DCM) to afford a yellow oilwhich was further purified by reverse-phase silica gel chromatography(10-45% water/CH₃CN (0.1% TFA)). The enriched fractions were collected,concentrated, neutralized with sat'd NaHCO₃ and extracted with EtOAc(3×). The organic phases were combined, dried (Na₂SO₄) and concentratedto dryness to afford a white foam. The foam was dissolved in CH₃CN/H₂O,frozen and lyophilized overnight to affordN-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamideas a white solid. (0.246 g, 16%). ¹H NMR (400 MHz, DMSO-d₆): 10.96 (s,1H), 8.97 (s, 1H), 8.20 (d, J=2.9 Hz, 1H), 8.11 (d, J=5.8 Hz, 1H), 8.06(d, J=9.0 Hz, 1H), 7.70 (dd, J=9.0, 2.9 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H),6.62 (dd, J=5.8, 2.4 Hz, 1H), 3.84-3.76 (m, 2H), 3.53-3.45 (m, 4H),3.41-3.36 (m, 2H), 3.26 (s, 3H), 2.88 (s, 6H); MS (ESI) m/z: 444.2(M+H⁺).

Example 117

A 0° C. solution of phosgene (15% in toluene, 1.77 mL, 2.52 mmol) wastreated drop-wise with a solution of pyridine (0.226 mL, 2.80 mmol) andExample B18 (158 mg, 1.23 mmol) in DCM (2 mL), warmed to RT, stirred for1 h, then concentrated to dryness. The residue was dissolved in DCM (2mL) and added drop-wise to a 0° C. solution of Example A25 (150 mg,0.559 mmol) and pyridine (0.226 mL, 2.80 mmol), in DCM (2 mL). Thereaction mixture was stirred at 0° C. for 15 min, then at roomtemperature for 22 h. The mixture was diluted with EtOAc (30 mL) and ½saturated sodium bicarbonate (30 mL). The organic phase was washed withbrine (30 mL), dried over sodium sulfate, and evaporated at reducedpressure. The residue was purified by chromatography (0-10% MeOH/EtOAc).The resultant material was dissolved in MeCN (2 mL) and then dilutedwith water (4 mL). The solution was quickly frozen and lyophilized,overnight to provide3-ethyl-N-(5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(26 mg, 10%). ¹H NMR (400 MHz, DMSO-d₆): δ 11.01 (s, 1H), 8.48 (d, J=5.7Hz, 1H), 8.26 (d, J=2.9 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.76 (dd,J=9.0, 3.0 Hz, 1H), 7.64 (s, 1H), 7.16 (d, J=2.5 Hz, 1H), 6.91 (dd,J=5.7, 2.5 Hz, 1H), 3.81 (t, J=8.2 Hz, 2H), 3.46 (t, J=8.2 Hz, 2H), 3.26(q, J=7.3 Hz, 2H), 2.46 (s, 3H), 1.09 (t, J=7.2 Hz, 3H). MS (ESI) m/z:409.2 (M+H⁺).

Example 118

A solution of phosgene (15% in toluene, 2.41 mL, 3.42 mmol) was cooledto 0° C. A solution of pyridine (0.277 mL, 3.42 mmol) and Example B18(158 mg, 1.23 mmol) in DCM (2 mL) was added drop-wise over 5 min. Thereaction mixture was stirred for 1 h at RT and was evaporated at reducedpressure to near dryness. The residue was dissolved in DCM (2 mL) andadded drop-wise to a 0° C. of Example A26 (150 mg, 0.559 mmol) andpyridine (0.277 mL, 3.42 mmol), in THF (2 mL). The reaction mixture wasstirred at 0° C. for 15 min and at RT for 22 h. The mixture was dilutedwith EtOAc (30 mL) and half-saturated sodium bicarbonate (30 mL). Theorganic phase was washed with brine (30 mL), dried over sodium sulfate,and evaporated under reduced pressure. The residue was purified bysilica gel chromatography (0-10% MeOH/EtOAc). The enriched fractionswere combined and further purified by reverse phase silica gelchromatography (20-50% MeCN/water (0.1% TFA) to provide3-ethyl-N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide(141 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆): δ 10.92 (s, 1H), 9.10 (d,J=2.3 Hz, 1H), 8.52 (d, J=5.7 Hz, 1H), 8.28 (dd, J=8.1, 2.4 Hz, 1H),7.91 (d, J=8.8 Hz, 1H), 7.64 (d, J=8.8 Hz, 1H), 7.58 (d, J=2.4 Hz, 1H),7.33 (d, J=8.2 Hz, 1H), 6.77 (dd, J=5.7, 2.4 Hz, 1H), 3.80 (t, J=8.3 Hz,2H), 3.46 (t, J=8.2 Hz, 2H), 3.26 (q, J=7.3 Hz, 2H), 2.50 (s, 3H), 2.26(s, 3H), 1.09 (t, J=7.2 Hz, 3H). MS (ESI) m/z: 433.2 (M+H⁺).

Example 119

A mixture of Example C1 (0.300 g, 0.718 mmol), acetamide (0.127 g, 2.154mmol), Cs₂CO₃ (0.468 g, 1.436 mmol) and Xantphos (0.046 g, 0.079 mmol)in dioxane (7 mL) was sparged with Ar under sonication. Pd₂(dba)₃ 0.053g, 0.057 mmol) was added, and the mixture was sparged again with Ar andheated at 93° C. overnight. The mixture was cooled to RT, andpartitioned with EtOAc and brine. The aqueous layer was extracted withEtOAc (3×) and the combined organics were dried over Na₂SO₄,concentrated to dryness and purified by silica gel chromatography(MeOH/DCM). The material was suspended in 4:1 MeCN/water, frozen andlyophilized overnight, and further dried in a drying oven to affordN-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(0.287 g, 90%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.98 (s,1H), 10.57 (s, 1H), 8.23 (dd, J=2.9, 0.5 Hz, 1H), 8.19 (d, J=5.7 Hz,1H), 8.08 (dd, J=9.0, 0.5 Hz, 1H), 7.72 (dd, J=9.0, 2.9 Hz, 1H), 7.66(d, J=2.3 Hz, 1H), 6.69 (dd, J=5.7, 2.4 Hz, 1H), 3.94-3.79 (m, 5H),3.49-3.37 (m, 4H), 2.04 (s, 3H), 1.78-1.67 (m, 2H), 1.64-1.58 (m, 2H);MS (ESI) m/z: 441.2 (M+H⁺).

Example 120 A mixture of Example C1 (0.150 g, 0.359 mmol), N,N-dimethylurea (0.190

g, 2.154 mmol), Cs₂CO₃ (0.292 g, 0.897 mmol) and Xantphos (0.062 g,0.108 mmol) in dioxane (7 mL) was sparged with Ar, treated Pd₂(dba)₃(0.043 g, 0.047 mmol), sparged again with Ar and heated at 100° C.overnight. The mixture was cooled to RT, treated with aqueous saturatedNaHCO₃, and extracted with EtOAc (3×). The combined organics were driedover Na₂SO₄, concentrated to dryness and purified via silica gelchromatography (MeOH/DCM). The yellowish solid was re-purified viareverse-phase chromatography (MeCN/H₂O with 0.1% TFA). The organics wereremoved under reduced pressure, the aqueous residue neutralized withsatd. NaHCO₃ and extracted with EtOAc (3×). The combined organics weredried over Na₂SO₄, concentrated to dryness and dried in vacuo. Theresidue was dissolved in 4:1 MeCN/water, frozen and lyophilizedovernight to affordN-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(110 mg, 54%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.96 (s,1H), 8.90 (s, 1H), 8.20 (d, J=2.5 Hz, 1H), 8.10 (J=5.7 Hz, 1H), 8.06 (d,J=9.0 Hz, 1H), 7.69 (dd, J=9.0, 2.9 Hz, 1H), 7.37 (d, J=2.4 Hz, 1H),6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.93-3.77 (m, 5H), 3.47-3.35 (m, 4H), 2.87(s, 6H), 1.76-1.65 (m, 2H), 1.62-1.56 (m, 2H); MS (ESI) m/z: 470.2(M+H⁺).

Example 121 To a degassed solution of Example C3 (0.12 g, 0.278 mmol) indioxane (3

mL) was added acetamide (0.066 g, 1.111 mmol), Cs₂CO₃ (0.091 g, 0.278mmol), X-Phos (0.013 g, 0.028 mmol), Pd₂(dba)₃ (0.025 g, 0.028 mmol) andthe mixture was stirred at 80° C. for 16 h. The mixture was diluted withEtOAc (5 mL) and filtered through a pad of diatomaceous earth. Thefilter pad was washed with EtOAc (3×8 mL). The combined filtrates werewashed with water and brine, dried (Na₂SO₄) and concentrated in vacuo.The residue was purified by chromatography (0-5% MeOH/DCM) to afford acolorless foam. The foam was dissolved in MeCN-water and the solutionwas frozen and lyophilized to provideN-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide(83 mg, 66%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.89 (s,1H), 10.54 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.88 (d, J=8.8 Hz, 1H), 7.60(d, J=8.8 Hz, 1H), 7.57 (d, J=2.4 Hz, 1H), 6.61 (dd, J=5.7, 2.4 Hz, 1H),3.93-3.78 (m, 5H), 3.48-3.33 (m, 4H), 2.20 (s, 3H), 2.02 (s, 3H),1.78-1.67 (m, 2H), 1.64-1.58 (m, 2H); MS (ESI) m/z: 455.1 (M+H⁺).

Example 122

A solution of Example B18 (0.088 g, 0.774 mmol) and pyridine (0.125 mL,1.549 mmol) in DCM (2 mL) was added to a solution of phosgene (15% intoluene, 1.021 g, 1.549 mmol) under argon. The reaction mixture wasstirred 15 minutes and then concentrated to dryness. The resultant solidwas dissolved in DCM (2 mL) and was treated with a solution of ExampleA28 (0.10 g, 0.387 mmol) and triethylamine (0.162 mL, 1.162 mmol) in THF(4 mL). The mixture was stirred for 1 h at RT, was diluted with water(30 mL) and 10% MeOH-DCM (30 mL). The layers were separated and theaqueous layer was extracted with DCM (10 mL). The combined organics werewashed with brine, dried (Na₂SO₄) and concentrated in vacuo. The residuewas purified by silica gel chromatography (1-15% MeOH/DCM) to afford afoam. The foam was dissolved in MeCN-water and solution was frozen andlyophilized. The resultant solid was treated with 60% EtOAc-hexanes (˜3mL) with stirring. The resultant suspension was collected by filtration,washed with 30% EtOAc-hexanes, and dried overnight to provideN-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide(84 mg, 54.5%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆): δ 10.90 (s,1H), 10.54 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.89 (d, J=8.8 Hz, 1H),7.58-7.57 (m, 2H), 6.61 (dd, J=5.7, 2.4 Hz, 1H), 3.82-3.78 (m, 2H),3.48-3.44 (m, 2H), 3.25 (q, J=7.2 Hz, 2H), 2.20 (s, 3H), 2.02 (s, 3H),1.09 (t, J=7.2 Hz, 3H); MS (ESI) m/z: 399.2 (M+H⁺).

The following assays demonstrate that certain compounds of Formula Iinhibit kinase activity of c-FMS kinase, c-KIT kinase, or PDGFRβ kinasein enzymatic assays and also inhibit the activity of c-FMS kinase inM-NFS-60 and THP-1 cell lines. In vivo evaluations of certain compoundsof Formula I also demonstrate inhibition of c-FMS in a pharmcodynamicmodel or also exhibit efficacy in a peritibial implant model, a U-251 orGL-261 glioma model, or in a MDA-MB-231 breast cancer xenograft model.

uFMS Kinase (Seq. ID No. 1) Assay

Activity of unphosphorylated c-FMS kinase (uFMS, Seq. ID no. 1) wasdetermined by following the production of ADP from the FMS kinasereaction with ATP and poly E4Y as substrates through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al.Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A340 nm) was continuously monitoredspectrophometrically. The reaction mixture (100 μL) contained FMS(purchased from Millipore) (10 nM), polyE4Y (1 mg/mL), MgCl₂ (10 mM),pyruvate kinase (4 units), lactate dehydrogenase (0.7 units),phosphoenol pyruvate (1 mM), NADH (0.28 mM) and ATP (500 μM) in 90 mMTris buffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Theinhibition reaction was started by mixing serial diluted test compoundwith the above reaction mixture. The absorption at 340 nm was monitoredcontinuously for 4 hours at 30° C. on Synergy 2 plate reader. Thereaction rate was calculated using the 3 to 4 h time frame. Percentinhibition was obtained by comparison of reaction rate with that of acontrol (i.e., in the absence of test compound). IC₅₀ values werecalculated from a series of percent inhibition values determined at arange of inhibitor concentrations using software routines as implementedin the GraphPad Prism software package.

uFMS Kinase sequence (Y538-end) used for screening (Seq. ID No. 1)YKYKQKPKYQ VRWKIIESYE GNSYTFIDPT QLPYNEKWEF PRNNLQFGKT LGAGAFGKVVEATAFGLGKE DAVLKVAVKM LKSTAHADEK EALMSELKIM SHLGQHENIV NLLGACTHGGPVLVITEYCC YGDLLNFLRR KAEAMLGPSL SPGQDPEGGV DYKNIHLEKK YVRRDSGFSSQGVDTYVEMR PVSTSSNDSF SEQDLDKEDG RPLELRDLLH FSSQVAQGMA FLASKNCIHRDVAARNVLLT NGHVAKIGDF GLARDIMNDS NYIVKGNARL PVKWMAPESI FDCVYTVQSDVWSYGILLWE IFSLGLNPYP GILVNSKFYK LVKDGYQMAQ PAFAPKNIYS IMQACWALEPTHRPTFQQIC SFLQEQAQED RRERDYTNLP SSSRSGGSGS SSSELEEESS SEHLTCCEQGDIAQPLLQPN NYQFCuKit Kinase (Seq. ID No. 2) Assay

Activity of unphosphorylated c-KIT kinase (uKIT, Seq. ID no. 2) wasdetermined by following the production of ADP from the KIT kinasereaction with ATP and poly E4Y as substrates through coupling with thepyruvate kinase/lactate dehydrogenase system (e.g., Schindler et al.Science (2000) 289: 1938-1942). In this assay, the oxidation of NADH(thus the decrease at A340 nm) was continuously monitoredspectrophometrically. The reaction mixture (100 μl) containedunphosphorylated KIT (12 nM), polyE4Y (1 mg/mL), MgCl₂ (10 mM), pyruvatekinase (4 units), lactate dehydrogenase (0.7 units), phosphoenolpyruvate (1 mM), and NADH (0.28 mM) and ATP (2000 μM) in 90 mM Trisbuffer containing 0.2% octyl-glucoside and 1% DMSO, pH 7.5. Theinhibition reaction was started by mixing serial diluted test compoundwith the above reaction mixture. The absorption at 340 nm was monitoredcontinuously for 4 hours at 30° C. on Synergy 2 plate reader (BioTech).Reaction rates around 3 to 4 h time frame were used to calculate %inhibitions, from which IC₅₀ values were generated.

uKit with N-terminal GST fusion used for screening (Seq ID No. 2)LGYWKIKGLV QPTRLLLEYL EEKYEEHLYE RDEGDKWRNK KFELGLEFPN LPYYIDGDVKLTQSMAIIRY IADKHNMLGG CPKERAEISM LEGAVDIRYG VSRIAYSKDF ETLKVDFLSKLPEMLKMFED RLCHKTYLNG DHVTHPDFML YDALDVVLYM DPMCLDAFPK LVCFKKRIEAIPQIDKYLKS SKYIWPLQGW QATFGGGDHP PKSDLVPRHN QTSLYKKAGS AAAVLEENLYFQGTYKYLQK PMYEVQWKVV EEINGNNYVY IDPTQLPYDH KWEFPRNRLS FGKTLGAGAFGKVVEATAYG LIKSDAAMTV AVKMLKPSAH LTEREALMSE LKVLSYLGNH MNIVNLLGACTIGGPTLVIT EYCCYGDLLN FLRRKRDSFI CSKQEDHAEA ALYKNLLHSK ESSCSDSTNEYMDMKPGVSY VVPTKADKRR SVRIGSYIER DVTPAIMEDD ELALDLEDLL SFSYQVAKGMAFLASKNCIH RDLAARNILL THGRITKICD FGLARDIKND SNYVVKGNAR LPVKWMAPESIFNCVYTFESD VWSYGIFLWE LFSLGSSPYP GMPVDSKFYK MIKEGFRMLS PEHAPAEMYDIMKTCWDADP LKRPTFKQIV QLIEKQISES TNHIYSNLAN CSPNRQKPVV DHSVRTNSVGSTASSSQPLL VHDDVUnphosphorylated PDGFRβ (uPDGFRβ) Kinase (Seq. ID No. 3) Assay

Activity of unphosphorylated PDGFRβ kinase (uPDGFRβ, Seq. ID No. 3) wasdetermined by following the production of ADP from the kinase reactionwith ATP and poly E4Y as substrates through coupling with the pyruvatekinase/lactate dehydrogenase system (e.g., Schindler et al. Science(2000) 289: 1938-1942). In this assay, the oxidation of NADH (thus thedecrease at A340 nm) was continuously monitored spectrophometrically.The reaction mixture (100 μL) contained PDGFRβ (DeCode, 15.7 nM),polyE4Y (2.5 mg/mL), MgCl₂ (10 mM), pyruvate kinase (4 units), lactatedehydrogenase (0.7 units), phosphoenol pyruvate (1 mM) and NADH (0.28mM) and ATP (500 μM) in a 90 mM Tris buffer containing 0.2%octyl-glucoside and 1% DMSO, at pH 7.5. The inhibition reaction wasstarted by mixing serial diluted test compound with the above reactionmixture. The absorption at 340 nm was monitored continuously for 4 h at30° C. on a Polarstar Optima or Synergy 2 plate reader. The reactionrate was calculated using the 1.5 to 2.5 h time frame. Percentinhibition was obtained by comparison of reaction rate with that of acontrol (i.e., with no test compound). IC₅₀ values were calculated froma series of percent inhibition values determined at a range of inhibitorconcentrations using software routines as implemented in the GraphPadPrism software package.

uPDGFRβ Kinase Sequence (residues 557-1106) used for screening (Seq IDNo. 3) QKKPRYEIRW KVIESVSSDG HEYIYVDPMQ LPYDSTWELP RDQLVLGRTL GSGAFGQVVEATAHGLSHSQ ATMKVAVKML KSTARSSEKQ ALMSELKIMS HLGPHLNVVN LLGACTKGGPIYIITEYCRY GDLVDYLHRN KHTFLQHHSD KRRPPSAELY SNALPVGLPL PSHVSLTGESDGGYMDMSK DESVDYVPML DMKGDVKYAD IESSNYMAPY DNYVPSAPER TCRATLINESPVLSYMDLVG FSYQVANGME FLASKNCVHR DLAARNVLIC EGKLVKICDF GLARDIMRDSNYISKGSTFL PLKWMAPESI FNSLYTTLSD VWSFGILLWE IFTLGGTPYP ELPMNEQFYNAIKRGYRMAQ PAHASDEIYE IMQKCWEEKF EIRPPFSQLV LLLERLLGEG YKKKYQQVDEEFLRSDHPAI LRSQARLPGF HGLRSPLDTS SVLYTAVQPN EGDNDYIIPL PDPKPEVADEGPLEGSPSLA SSTLNEVNTS STISCDSPLE PQDEPEPEPQ LELQVEPEPE LEQLPDSGCPAPRAEAEDSF L

Using the enzymatic protocols described above, compounds of Formula Iare shown to be inhibitors in assays measuring the kinase activity ofuFMS kinase, uKIT kinase, or uPDGFRβ kinase, as indicated below in Table1.

TABLE 1 Activity of Compounds of Formula I in Enyzmatic Assays of uFMSkinase, uKIT kinase, or uPDGFRβ kinase. Example uFMS uKIT uPDGFRβ 1 +++++++ ++ 2 +++ +++ + 3 ++++ ++ + 4 +++ +++ ++ 5 +++ NT ++ 6 +++ NT NT 7+++ +++ + 8 +++ NT NT 9 +++ NT NT 10 +++ ++ + 11 +++ +++ + 12 +++ +++ +13 +++ NT NT 14 +++ NT + 15 ++++ NT +++ 16 ++++ ++++ ++ 17 +++ NT NT 18+++ ++ + 19 +++ +++ + 20 +++ ++ + 21 +++ +++ + 22 ++++ +++ + 23 +++ + +24 +++ +++ ++ 25 ++++ ++++ +++ 26 ++++ +++ + 27 ++++ NT + 28 ++++ ++ +29 ++++ ++++ + 30 ++++ ++++ ++ 31 +++ ++ + 32 ++ ++ + 33 ++++ ++++ ++ 34++++ ++++ +++ 35 ++++ ++ ++ 36 ++++ +++ ++ 37 +++ ++ + 38 +++ ++++ NT 39+++ ++ + 40 ++++ +++ NT 41 +++ + + 42 ++++ ++ + 43 ++++ ++ + 44 +++ ++ +45 ++++ +++ + 46 ++++ +++ ++ 47 ++++ ++ + 48 ++++ ++++ ++ 49 +++ + + 50+++ +++ + 51 +++ +++ + 52 +++ +++ ++ 53 +++ + + 54 +++ ++ ++ 55 ++ + +56 +++ + + 57 ++++ + + 58 +++ + + 59 ++++ +++ ++ 60 +++ +++ ++ 61 ++++++ + 62 ++ ++ NT 63 ++ + NT 64 ++ + NT 65 +++ ++ NT 66 +++ ++ NT 67 ++ +NT 68 ++++ +++ + 69 +++ +++ + 70 +++ ++ + 71 ++++ +++ ++ 72 ++++ +++++++ 73 ++ + NT 74 +++ ++ NT 75 ++++ ++ NT 76 +++ ++ NT 77 +++ +++ NT 78+++ + NT 79 ++ ++ NT 80 ++++ ++ + 81 +++ + NT 82 +++ ++++ NT 83 +++ +++++ 84 +++ +++ + 85 ++++ +++ + 86 ++++ +++ + 87 ++++ +++ NT 88 +++ ++ +89 ++ ++ + 90 ++++ +++ +++ 91 ++++ ++ NT 92 ++++ +++ NT 93 +++ NT NT 94+++ NT NT 95 +++ NT NT 96 +++ NT NT 97 +++ NT NT 98 ++ NT NT 99 +++ NTNT 100 +++ NT NT 101 ++++ NT ++ 102 +++ NT NT 103 +++ NT + 104 ++ NT +105 +++ NT + 106 +++ NT + 107 ++++ NT ++ 108 +++ NT + 109 +++ +++ + 110++++ NT + 111 ++++ NT + 112 +++ +++ ++ 113 ++++ +++ NT 114 + + NT 115 ++++ + 116 +++ +++ + 117 ++ ++ + 118 +++ + + 119 +++ ++ ++ 120 ++++ ++++++ 121 +++ ++ ++ 122 +++ + + NT: Not Tested; +: IC₅₀ > 1 uM; ++: 0.1 uM< IC₅₀ ≦ 1 uM; +++: 0.01 uM < IC₅₀ ≦ 0.1 uM; ++++: IC₅₀ ≦ 0.01 uM

M-NFS-60 Cell Culture

M-NFS-60 cells (catalog #CRL-1838) were obtained from the American TypeCulture Collection (ATCC, Manassas, Va.). Briefly, cells were grown insuspension in RPMI 1640 medium supplemented with 10% characterized fetalbovine serum (Invitrogen, Carlsbad, Calif.), 0.05 mM 2-mercaptoethanol,and 20 ng/mL mouse recombinant macrophage colony stimulating factor(M-CSF) at 37° C., 5% CO₂, and 95% humidity. Cells were allowed toexpand until reaching saturation at which point they were subcultured orharvested for assay use.

M-NFS-60 Cell Proliferation Assay

A serial dilution of test compound was dispensed into a 384-well blackclear bottom plate (Corning, Corning, N.Y.). Two thousand five hundredcells were added per well in 50 μL complete growth medium. Plates wereincubated for 67 h at 37° C., 5% CO₂, and 95% humidity. At the end ofthe incubation period 10 μL of a 440 μM solution of resazurin (Sigma,St. Louis, Mo.) in PBS was added to each well and incubated for anadditional 5 h at 37° C., 5% CO₂, and 95% humidity. Plates were read ona Synergy2 reader (Biotek, Winooski, Vt.) using an excitation of 540 nMand an emission of 600 nM. IC₅₀ values were calculated from a series ofpercent inhibition values determined at a range of inhibitorconcentrations using software routines as implemented in the GraphPadPrism software package.

THP-1 Cell Culture

THP-1 cells (catalog #TIB-202) were obtained from the ATCC. Briefly,cells were grown in RPMI 1640 supplemented with 10% characterized fetalbovine serum, 1% sodium pyruvate, 1% Penicillin-Streptomycin-Glutamine(PSG) and 55 uM 2-mercaptoethanol (Invitrogen, Carlsbad, Calif.) at 37degrees Celsius, 5% CO₂, 95% humidity. Cells were allowed to expanduntil reaching 70-95% confluency at which point they were subcultured orharvested for assay use.

Phospho-FMS ELISA Assay

A serial dilution of test compound was diluted 1:100 in assay medium(RPMI 1640 supplemented with 10% characterized fetal bovine serum) in a96 well black clear bottom plate (Corning, Corning, N.Y.). In a separate96 well black clear bottom plate, one hundred and fifty thousand THP-1cells were added per well in 100 μL in assay medium. Fifty microlitersof diluted compound was then added to the cells. Plates were incubatedfor 4 hours at 37 degrees Celsius, 5% CO₂, 95% humidity. At the end ofthe incubation period, cells were stimulated with 50 μL of a 100 nMsolution of recombinant human M-CSF (catalog #216-MC, R & D Systems,Minneapolis, Minn.) in assay medium and the plate was incubated for 5minutes at 37 degrees Celsius, 5% CO₂, 95% humidity. Lysates wereprepared and used to perform the phospho-FMS ELISA as described by themanufacturer (catalog #DYC3268, R & D Systems, Minneapolis, Minn.).GraphPad Prism was used to calculate IC₅₀ values obtained from datagenerated from the ELISA assay.

Osteoclast Tartrate-Resistant Acid Phosphatase Assay

A serial dilution of test compound was dispensed into a 384-well blackclear bottom plate (Nalge Nunc International, Rochester, N.Y.). Compoundwas diluted by the addition of DMEM media supplemented with 10%characterized fetal bovine serum (Invitrogen, Carlsbad, Calif.). Dilutedcompound was transferred to a 384-well black clear bottom plate.Two-thousand five hundred osteoclast precursors (Lonza, Walkersville,Md.) were added per well in growth media containing Receptor Activatorof Nuclear Factor Kappa-beta ligand (RANKL) and M-CSF (R&D Systems,Minneapolis, Minn.). Plates were incubated for 7-14 days at 37 degreesCelsius, 5% CO₂, and 95% humidity to allow differentiation of osteoclastprecursors. At the end of the incubation period, 10 μL of supernatantfrom each well was transferred to a clear 384-well plate.Tartrate-resistant acid phosphatase activity in the supernatant sampleswas determined using an acid phosphatase assay kit (Sigma, St. Louis,Mo.). Absorbance was measured at 550 nm using a plate reader. Data wasanalyzed using Prism software (Graphpad, San Diego, Calif.) to calculateIC₅₀ values.

The compounds of Formula I are demonstrated to be functional inhibitorsin one or more of the cellular assays described above, as indicated inTable 2.

TABLE 2 Inhibitory effects of compounds of Formula I versus M-NFS-60,THP-1 and Osteoclast Cells M-NFS-60 cell Osteoclast pFMS inhibition inExample proliferation assay THP-1 cells 1 +++ +++ +++ 2 +++ ++++ NT 3+++ +++ +++ 4 +++ +++ ++++ 5 +++ +++ ++ 6 +++ NT NT 7 +++ +++ +++ 8 +++++ +++ 9 ++ +++ +++ 10 +++ +++ ++++ 11 +++ ++++ +++ 12 +++ ++++ +++ 13++ +++ NT 14 ++ +++ ++ 15 ++++ ++++ +++ 16 +++ ++++ +++ 17 +++ +++ NT 18++ +++ +++ 19 +++ +++ +++ 20 +++ +++ +++ 21 +++ +++ +++ 22 ++++ ++++ +++23 +++ +++ +++ 24 +++ +++ NT 25 ++++ ++++ +++ 26 ++++ +++ +++ 27 +++++++ NT 28 +++ ++++ +++ 29 ++++ ++++ +++ 30 ++++ ++++ NT 31 + NT NT 33+++ +++ ++++ 34 +++ +++ ++++ 35 +++ ++++ ++++ 36 ++++ ++++ ++++ 37 ++++++ +++ 38 +++ ++++ NT 39 ++ +++ +++ 40 +++ NT NT 41 ++ +++ +++ 42 +++++++ +++ 43 ++++ ++++ +++ 44 ++ +++ NT 45 +++ ++++ NT 46 +++ ++++ NT 47+++ ++++ NT 48 +++ ++++ NT 49 ++ +++ ++ 50 +++ +++ NT 51 +++ ++ NT 52+++ +++ ++ 53 +++ ++ NT 54 +++ +++ ++ 55 ++ ++ NT 56 +++ ++ ++ 57 +++++++ +++ 58 +++ +++ +++ 59 ++++ ++++ NT 60 +++ +++ NT 61 ++++ ++++ ++++62 ++ ++ NT 63 + + NT 64 + + NT 65 ++ +++ NT 66 ++ ++ NT 67 ++ ++ NT 68+++ ++++ NT 69 ++ +++ NT 70 ++ +++ NT 71 +++ +++ NT 72 ++++ ++++ NT 73 +++ NT 74 ++ +++ NT 75 +++ +++ NT 76 ++ ++ NT 77 ++ ++ NT 78 + ++ NT 79 +++ NT 80 +++ +++ NT 81 ++ ++ NT 82 +++ +++ NT 83 +++ +++ NT 84 +++ +++NT 85 +++ ++++ +++ 86 ++++ ++++ NT 87 +++ +++ NT 88 +++ +++ +++ 89 + ++NT 90 +++ +++ NT 91 +++ +++ +++ 92 +++ +++ +++ 93 ++ +++ NT 94 ++ ++ +++95 +++ +++ NT 96 + ++ +++ 97 ++ ++ ++ 98 ++ +++ NT 99 +++ +++ NT 100 +++++ NT 101 +++ ++++ +++ 102 + ++ NT 103 ++ ++ NT 104 + ++ NT 105 ++ +++NT 106 + ++ NT 107 +++ +++ NT 108 ++ ++ NT 109 +++ ++ NT 110 +++ NT NT111 +++ ++++ NT 112 ++ NT NT 113 ++ NT NT 115 + +++ NT 116 ++ +++ NT 117++ +++ +++ 118 +++ +++ +++ 119 +++ +++ +++ 120 +++ ++++ +++ 121 ++ ++ NT122 ++ ++ NT NT: Not Tested; +: IC₅₀ > 1 uM; ++: 0.1 uM < IC₅₀ ≦ 1 uM;+++: 0.01 uM < IC₅₀ ≦ 0.1 uM; ++++: IC₅₀ ≦ 0.01 uM

Measurements of In Vivo Activity

Analysis of cFOS mRNA Production in a c-FMS Mouse Spleen PharmacodynamicModel

To examine the in vivo modulation of FMS activity by compounds offormula I, spleen samples from female DBA/1 mice were collected andanalyzed for M-CSF stimulated production of cFOS mRNA. Briefly, six toseven week old female Taconic DBA/1BO J Bom Tac mice were treated with asingle oral dose (by gavage) of either vehicle or compound. Plasma andspleen samples were collected from four mice at each timepoint 2, 4, 6,8, 12, 18, and 24 hours after dosing. Fifteen minutes prior toeuthanasia, all mice were injected IV with 1 μg (100 μL fixed volume) ofM-CSF. M-CSF, Recombinant Mouse Macrophage Colony Stimulating Factor(36.4 kDa homodimer, ≧98% purity) was obtained from Gibco. Allprocedures carried out in this experiment were conducted in compliancewith all the laws, regulations and guidelines of the National Institutesof Health (NIH). cFOS mRNA levels in spleen extracts were determinedusing a quantitative reverse transcriptase PCR kit from LifeTechnologies. Plasma levels of FMS inhibitors were determined by massspectrometer analysis. The degree of FMS inhibition was correlative tothe amount of decrease observed in cFOS mRNA levels in the spleensamples of treated animals compared to vehicle.

In this model, Examples 18, 41, 42, and 118 afforded ≧70% inhibition ofcFOS mRNA levels out to 8 h post 30 mg/kg dose.

PC-3 Peritibial Implant Model of Cancer Bone Metastasis

To evaluate in vivo anti-cancer activity of compounds of formula I, thePC-3 M-luc peritibial injection model of bone invasiveness model wasemployed. Briefly, PC-3 M-luc cells were obtained from XenogenCorporation (Caliper Life Sciences) and expanded using MEM mediamodified with L-Glutamine (Cell Grog #10-045-CV) supplemented with 10%fetal bovine serum, 1% penicillin-streptomycin-glutamine, 1%non-essential amino acids, and 1% MEM vitamins in 5% CO₂ atmosphere at37° C. Six to 7 week old male nude mice (Cr1:NU-Foxn1nu) were obtainedfrom Charles River Laboratories. Test mice were implanted peritibiallyon Day 0 with 1×10⁶ cells/mouse (0.1 ml) using an insulin syringe with afixed 28-gauge needle. The needle was inserted at the ankle between thetibia and fibula until the bevel of the needle reached approximatelyhalf way between the knee and ankle. Treatments began on Day 0. Animalswere dosed by oral gavage twice daily for the study duration. Allprocedures carried out in this experiment were conducted in compliancewith all the laws, regulations and guidelines of the National Institutesof Health (NIH). When the primary tumor reached approximately 800 mg insize, ex-vivo micro-CT was performed on the tumor bearing fixed hindlimb samples using a GE RS150 small animal micro-CT scanner using withthe following settings:

X-ray tube voltage=70 kVp

X-ray tube current=25 mA

Exposure time=20 ms

Number of frames=500

Angle increment between frames=0.4o

Number of averages per frame=2

Acquisition method=Parker

Images were then reconstructed at high resolution (100 microns;isotropic).

Isosurface volume renderings were used to delineate lesions in the hindlimbs. A constant threshold was used to produce consistentrepresentation of the isosurface between different anatomical sites andsamples. Lesions in the right hind limb were scored with values of 0, 1,2, 3, or 4 based on a qualitative assessment of lesion size as definedby:

0: Normal Bone

1: Minimal lesions. Some roughening of the isosurface. Small areas ofapparent bone resorption.

2: Mild. More numerous lesions. Significant roughening of theisosurface. Full thickness lesions apparent.

3: Moderate. Full thickness lesions larger and more numerous.

4: Marked. Many, large, full thickness lesions. Significant distortionof remaining structure. Marked bone loss.

Example 42 was evaluated in this model at an oral dose of 30 mg/kg twicedaily and demonstrated positive benefit with a lesion score of 2compared to a lesion score of 4 in vehicle-treated animals.

U251 Intra-Cerebro-Ventricular Implant in Mice

To evaluate in vivo anti-cancer activity compounds of Formula I incombination with fractionated, localized head radiation, an orthotopicU251-luc (Luc) human glioma carcinoma model in female outbred nu/nu miceis employed. Briefly, U251 cells are obtained from the ATCC and alteredto be luciferase expressing. They are grown in RPMI 1640 Mediasupplemented with 10% FBS and 1% PSG. The growth environment ismaintained in an incubator with a 5% CO₂ atmosphere at 37° C. FemaleHarlan Nude mice (Hsd:AthymicNude-Fox1nu) 8-9 weeks old are used in thisstudy. Test animals are implanted intracranially with U251-luc(LucmCherry) cells. Briefly, animals are injected subcutaneously with 5mg/kg carprofen and anesthetized using 2% isoflurane in air. The animalsare then secured in a stereotaxic frame (ASIinstruments, Inc.) and ahole drilled 2 mm right lateral, 1 mm anterior to the coronal suture.The cell suspension (stored on wet ice) is mixed thoroughly and drawn upinto a 50 μl syringe. The syringe needle is centered over the burr holeand lowered 3 mm into the brain and retracted 1 mm to form a “reservoir”for the deposition of the cell suspension. 10 μl of the cell suspension(1×10⁶ cells/mouse) is then injected slowly into the brain tissue. Thetumor progression is tracked with in vivo bioluminescence imagingperformed using an IVIS 50 optical imaging system (Xenogen, Alameda,Calif.). Bioluminescence images are acquired at periodic intervals fortumor burden estimation. All procedures carried out in this experimentare conducted in compliance with all the laws, regulations andguidelines of the National Institutes of Health (NIH). Treatment beginswhen the mean brain bioluminescence signal for all groups in theexperiment is ˜1.3×109 photons/sec (typically 9 days post-implant). Allmice receive 2 Gy of radiation each day for five consecutive days from aRadSource RS-2000 irradiator. Additionally, mice receive test compounddosed by oral gavage or optionally with co-administered bevacizumab bytail vein injection. Bioluminescence images are acquired generally ondays 8, 10, 14, 17, 21, 22, 24, 28 and 35 post-implant for tumor burdenestimation. For each measurement, each mouse is injected subcutaneouslywith 150 mg/kg D-Luciferin (Promega) and imaged 10 minutes after theinjection. Images are analyzed using Living Image (Xenogen, Alameda,Calif.) software. The BLI signal in the brain is calculated with a fixedarea ROI to estimate the tumor burden. Average BLI signal for each groupis compared to vehicle control to determine therapeutic benefit.Twenty-eight days after the first radiation treatment mice areeuthanized, via over-exposure to carbon dioxide, for blood and braincollection. Whole blood is collected via terminal cardiac puncture andplaced into EDTA Microtainer® tubes. Brains are excised and placed into10% neutral buffered formalin.

GL261 Intracranial Implant Model

To evaluate the in vivo anti-cancer activity of compounds of formula I,an intracranial implant of GL261-luc2 murine glioma is employed. BrieflyGL261-luc2 cells are obtained from Caliper Life Sciences, Inc andexpanded in Dulbecco's Modified Eagle Media (DMEM) which is supplementedwith 10% FBS and 1% PSG. The growth environment is maintained in anincubator with a 5% CO₂ atmosphere at 37° C. Following expansion, cellsare re-suspended using serum-free media to generate a concentration of1×10⁸ cells/mL. Six to seven week old female C57BL/6J-Tyrc-2J/J fromJackson Labs are implanted intracranially on Day 0 with GL261-luc2cells. For aseptic surgical implantation, animals are injectedsubcutaneously with 5 mg/kg carprofen, anesthetized using 2% isofluranein air. The animals are then secured in a stereotaxic frame(ASIinstruments, Inc.) and a hole is drilled 2 mm right lateral, 1 mmanterior to the coronal suture. The cell suspension (stored on wet ice)is mixed thoroughly and drawn up into a 50 μL syringe. The syringeneedle is centered over the burr hole and lowered 3 mm into the brainand retracted 1 mm to form a “reservoir” for the deposition of the cellsuspension. 10 μL of the cell suspension (1×10⁶ cells/mouse) is theninjected slowly into the brain tissue. The tumor progression is trackedwith in vivo bioluminescence imaging performed using an IVIS 50 opticalimaging system (Xenogen, Alameda, Calif.). Bioluminescence images areacquired at periodic intervals for tumor burden estimation. The quantityof emitted light from the tumor after systemic injection of D-Luciferinis expected to correlate with tumor size. Each mouse is injectedintraperitoneally (IP) with 150 mg/kg D-Luciferin and imaged in theprone position 10 minutes after the injection. Medium and small binningof the CCD chip is used, and the exposure time is adjusted (10 secondsto 1 minute) to obtain at least several hundred counts from the tumorsand to avoid saturation of the CCD chip. Images are analyzed usingLiving Image (Xenogen, Alameda, Calif.) software. Each unique signal iscircled manually and labeled by group and mouse number. Treatment beginsby oral gavage of test compound when the mean brain bioluminescencesignal for all groups in the experiment is 280×10⁶ photons/sec. Allprocedures carried out in this experiment are conducted in compliancewith all the laws, regulations and guidelines of the National Institutesof Health (NIH). At the end of study all mice are euthanized viaover-exposure to carbon dioxide for blood and brain collection. Wholeblood is collected via terminal cardiac puncture and placed into EDTAMicrotainer® tubes. Brains are excised and placed into 10% neutralbuffered formalin.

MDA-MB-231 Xenograft Study

To evaluate the in vivo anti-cancer activity compounds of formula I, aMDA-MB-231-luc-D3H2LN human breast carcinoma xenograft was employed.Briefly, MDA-MB-231-luc-D3H2LN cells were obtained from Xenogen andexpanded in Minimal Essential Media (MEM) with EBSS which was modifiedwith 1% L-glutamine and supplemented with 10% FBS, 1% PSG, 1%non-essential amino acids, and 1% sodium pyruvate. The growthenvironment was maintained in an incubator with a 5% CO₂ atmosphere at37° C. Cells were harvested and re-suspended using 50% serum-free mediaand 50% Matrigel® to generate a stock concentration of 5×10⁶ cells/mL.

Six to 7 week old female C.B-17/IcrHsd-PrkdcscidLystbg mice wereinjected with 200 μL of cell suspension subcutaneously, just below theright axilla. All procedures carried out in this experiment wereconducted in compliance with all the laws, regulations and guidelines ofthe National Institutes of Health (NIH). Treatment began when the meantumor burden was approximately 150 mg. All mice were dosed with testcompound by oral gavage. Body weights and tumor measurements wererecorded three times weekly. Tumor burden (mg) was estimated fromcaliper measurements by the formula for the volume of a prolateellipsoid assuming unit density as: Tumor burden (mg)=(L×W2)/2, where Land W were the respective orthogonal tumor length and width measurements(mm) The primary endpoints to evaluate efficacy was % T/C. % T/C wasdefined as the median tumor mass of a Treated Group divided by themedian tumor mass of the Control Group×100. Ex vivo bioluminescenceimaging was performed as animals exited the study, using an IVIS 50optical imaging system (Xenogen, Alameda, Calif.). Animals were injectedIP with 150 mg/kg D-Luciferin (Promega) and euthanized 10 minutesfollowing the injection. The primary tumor was removed and snap frozenfor future analysis and the mouse opened and imaged in the supineposition. Large binning of the CCD chip was used, and the exposure timewas adjusted (1 to 2 minutes) to obtain at least several hundred countsfrom the tumors and to avoid saturation of the CCD chip. Images wereanalyzed using Living Image (Xenogen, Alameda, Calif.) software. Eachunique signal was circled manually and labeled by group and mousenumber. Total BLI signal was correlative to tumor size and compared tovehicle control to determine treatment benefit.

Example 18 exhibited 51% tumor growth inhibition in this model whenorally dosed at 30 mg/kg twice daily.

Compounds with structures similar to certain compounds of Formula I havebeen previously disclosed in US2008/0255155 as inhibitors of VEGFR (KDR)and cMET kinases. Representative examples are shown below. In addition,US2008/0255155 Examples 3 and 5 have also been reported to be inhibitorsof TRK-A kinase (S. L. Raeppel, et. al. Internationl Journal ofMedicinal Chemistry (2012) Article ID 412614). Neither publicationdisclosed activity of any of the compounds below against c-FMS, c-KIT orPDGFR-b kinases or teach that the compounds possessed such activity. Thecompounds of US2008/0255155 differ from the compounds of Formula I bythe presence of an aromatic “A” moiety (e.g. left-most aryl ring instructures shown below). Published data from US2008/0255155 related tothe inhibitory activity of these compounds against cMET and KDR kinasesare collected in Table 3 below.

TABLE 3 Entry Compound cMET IC₅₀ KDR IC₅₀ 1 US2008/0255155, Ex 3 <250 nM<250 nM 2 US2008/0255155, Ex 5 <250 nM <500 nM 3 US2008/0255155, Ex 6<250 nM <250 nM 4 US2008/0255155, Ex 10 <250 nM <250 nM 5US2008/0255155, Ex 11 <250 nM <250 nM 6 US2008/0255155, Ex 12 <250 nM<250 nM 7 US2008/0255155, Ex 70 <500 nM <500 nM 8 US2008/0255155, Ex 71<1000 nM >1000 nM

Data for compound A, which contains a phenyl “A-ring” similar to thecompounds of US2008/0255155, as well as compounds of the presentinvention are shown below. Surprisingly, compounds of Formula I (A isnon-aromatic moiety) potently inhibit c-FMS kinase but do not readilyinhibit cMET or KDR kinases, as illustrated in Table 4. Such resultscould not have been predicted from the teachings of US2008/0255155.

TABLE 4 Entry Compound c-FMS IC₅₀ cMET IC₅₀ KDR IC₅₀ 1 Compound A 13 nM196 nM 990 nM 2 Example 1 6 nM >5,000 nM >3,300 nM 3 Example 91 7nM >5,000 nM >3,300 nM 4 Example 15 3 nM 370 nM 670 nM 5 Example 18 20nM >5,000 nM >3,300 nM 6 Example 29 2 nM 898 nM >3,300 nM 7 Example 42 8nM >5,000 nM >10,000 8 Example 101 8 nM 4,000 >3,300 nM 9 Example 90 5nM >5,000 nM  3,300

EQUIVALENTS

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically in this disclosure. Suchequivalents are intended to be encompassed in the scope of the followingclaims.

1. A compound of Formula I,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof, wherein A is selected from the group consisting ofC1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain is partially orcompletely deuterated, branched C3-C8alkyl, fluoroC1-C6alkyl wherein thealkyl is fully or partially fluorinated, C3-C8carbocyclyl, and a 4-8membered heterocyclic ring, and wherein the A moiety may be furthersubstituted with one, two, or three R3 moieties; W is C5-C6heteroaryl,—NHC(O)R6, —NHC(O)R7, —NHC(O)N(R8)R9, —C(O)R11, or phenyl, wherein theC5-C6heteroaryl and phenyl moieties are optionally substituted by one,two, or three R5; each X1, X2, X3 and X4 is individually andindependently hydrogen, C1-C6 alkyl, halogen, or fluoro-C1-C6 alkylwherein the alkyl chain is partially or completely fluorinated; Z1 is Nor CX3; Z2 is CX4 or N; Z3 is CH or N; each R1 and R2 is individuallyand independently H, C1-C6 alkyl, fluoroC1-C6alkyl wherein the alkyl isfully or partially fluorinated, hydroxyl, C1-C6 alkoxy,fluoroC1-C6alkoxy wherein the alkyl group is fully or partiallyfluorinated, or cyano; each R3 is individually and independently H,halogen, C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain ispartially or completely fluorinated, branched C3-C8 alkyl, C3-C8cycloalkyl, C1-C6 alkoxy, fluoro-C1-C6 alkoxy wherein the alkyl chain ispartially or completely fluorinated, branched C3-C6 alkoxy, hydroxyl, orcyano; each R4 is individually and independently hydrogen, C1-C6 alkyl,or branched C3-C8 alkyl; each R5 is individually and independentlyhydrogen, C1-C6 alkyl, deutero-C1-C6 alkyl wherein the alkyl chain ispartially or completely deuterated, branched C3-C8 alkyl, halogen,cyano, fluoro-C1-C6 alkyl wherein the alkyl chain is partially orcompletely fluorinated, —(CH₂)_(m)—C(O)NR8(R9), —(CH₂)_(m)—C(O)R7,—(CH₂)_(m)—C(O)R6, —(CH₂)_(m)—CN, —(CH₂)_(m)—OR8, —(CH₂)_(m)—NR8(R9), or—(CH₂)_(m)—R7, wherein each alkylene may be further substituted with oneor more C1-C6alkyl; each R6 is individually and independently hydrogen,C1-C6 alkyl, branched C3-C8 alkyl, C3-C8 cycloalkyl, —(CH₂)_(m)—OR8,—(CH₂)_(m)—NR8(R9), or —(CH₂)_(m)—R7, wherein each alkylene may befurther substituted with one or more C1-C6alkyl; each R7 isindependently and individually selected from the group consisting of

and wherein the symbol (##) is the point of attachment to respective R5or R6 moieties containing a R7 moiety; each R7 is optionally substitutedwith —(R10)_(p); each R8 and R9 is individually and independently H,C1-C6 alkyl, fluoro-C1-C6 alkyl wherein the alkyl chain is partially orcompletely fluorinated, or branched C3-C8 alkyl; each R10 isindividually and independently C1-C6 alkyl, —(CH₂)_(m)—CN,—(CH₂)_(m)—OR3, —(CH₂)_(m)—NR8(R9), or —(CH₂)_(m)—C(O)—R6, wherein eachalkyl or alkylene is optionally substituted with one or two C1-C6 alkyl;R11 is —N(R8)R9 or R7; each m is individually and independently 0, 1, 2,or 3; each n is individually and independently 0, 1, 2, or 3; each p isindividually and independently 0, 1, 2, or 3; and each q is individuallyand independently 0, 1, 2, or
 3. 2. The compound of claim 1, wherein Wis selected from the group consisting of pyrazolyl, imidazolyl,isoxazolyl, oxazolyl, thiazolyl, triazolyl, pyridinyl, —NHC(O)R6,—NHC(O)R7, —NHC(O)N(R8)R9, —C(O)N(R8)R9 and phenyl.
 3. The compound ofclaim 2, wherein the compound is a compound of Formula Ia,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof, wherein the A moiety is selected from the groupconsisting of C1-C6 alkyl, branched C3-C8alkyl, fluoroC1-C6alkyl whereinthe alkyl is fully or partially fluorinated, C3-C8carbocyclyl, and a 4-8membered heterocyclic ring.
 4. The compound of claim 3, wherein W ispyrazolyl, optionally substituted with —(R5)_(p).
 5. The compound ofclaim 4, wherein Z1 is N and X1 and X2 are independently selected fromC1-C6alkyl and hydrogen.
 6. The compound of claim 4, wherein Z1 is CX3and X1, X2 and X3 are individually and independently halogen, hydrogen,or C1-C6 alkyl.
 7. The compound of claim 2, wherein the compound is acompound of Formula Ib,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof, wherein A is C1-C6 alkyl, branched C3-C8alkyl,fluoroC1-C6alkyl wherein the alkyl is fully or partially fluorinated,C3-C8carbocyclyl, or a 4-8 membered heterocyclic ring and q is 0 or 1.8. The compound of claim 7, wherein W is pyrazolyl, optionallysubstituted with —(R5)_(p).
 9. The compound of claim 8, wherein Z1 is Nand X1 and X2 are independently selected from C1-C6alkyl or hydrogen.10. The compound of claim 8, wherein Z1 is CX3 and X1, X2 and X3 areindividually and independently halogen, hydrogen, or C1-C6 alkyl. 11.The compound of claim 3, wherein the compound is a compound of FormulaIc,

or a pharmaceutically acceptable salt, enantiomer, stereoisomer, ortautomer thereof.
 12. The compound of claim 11, wherein W is pyrazolyl,optionally substituted with —(R5)_(p).
 13. The compound of claim 12,wherein Z1 is N and X1 and X2 are independently selected from C1-C6alkylor hydrogen.
 14. The compound of claim 12, wherein Z1 is CX3 and X1, X2and X3 are individually and independently halogen, hydrogen, or C1-C6alkyl.
 15. The compound of claim 1 selected from the group consisting ofN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,2-oxo-3-(tetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)imidazolidine-1-carboxamide,N-(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,dimethyltetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclohexyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-(1-methoxycyclopropyl)ethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide,3-cyclohexyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-(3-methoxy-3-methylbutyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(4,4-difluorocyclohexyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(4,4-difluorocyclohexyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)—N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,(R)—N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopentyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclohexyl-4,4-dimethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclohexyl-4,4-dimethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)—N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydrofuran-3-yl)imidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,4-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-methyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(6-methyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(cyanomethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-ethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(R)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-ethyl-5-((6′-methyl-[2,3′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-ethyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopentyl-N-(4,6-dimethyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-methyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-cyclopentyl-N-(6-ethyl-5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-methyl-N-(4-methyl-5-((2-(1-methyl-1-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,3-ethyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(4-methyl-5-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,4-((6-(3-(tert-butyl)-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide,N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2-fluoro-3-methyl-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(4-((2-(1H-pyrazol-4-yl)pyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(3-chloro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(4-((2-acetamidopyridin-4-yl)oxy)-5-chloro-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(2,5-difluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-(1-methoxycyclopropyl)ethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-4-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(3-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxypropyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(oxetan-3-yl)-2-oxoimidazolidine-1-carboxamide,(S)—N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(1-methoxypropan-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(2-(trifluoromethoxy)ethyl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclohexyl-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(3-methoxy-3-methylbutyl)-2-oxoimidazolidine-1-carboxamide,N-(5-bromo-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(4,4-difluorocyclohexyl)-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-cyclopentyl-2-oxoimidazolidine-1-carboxamide,N-(5-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-3-(2-hydroxy-3,3-dimethylbutyl)-2-oxoimidazolidine-1-carboxamide,N-(3-chloro-2-fluoro-4-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)phenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-chloro-4-((2-(2-cyanoacetamido)pyridin-4-yl)oxy)-2-fluorophenyl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,4-((6-(3-ethyl-2-oxoimidazolidine-1-carboxamido)pyridin-3-yl)oxy)-N-methylpicolinamide,N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-3-(2-methoxyethyl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methyloxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2′-methyl-[2,4′-bipyridin]-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyrimidin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-acetamidopyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(3,3-dimethylureido)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,andN-(5-((2-acetamidopyridin-4-yl)oxy)-6-methylpyridin-2-yl)-3-ethyl-2-oxoimidazolidine-1-carboxamide.16. A pharmaceutical composition, comprising a compound of claim 15 anda pharmaceutically acceptable carrier.
 17. A compound selected from thegroup consisting of3-(tert-butyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(tert-butyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-isopropyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-methyl-N-(6-methyl-5-((2-(1-methyl-1-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-cyclopropyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(1-methylpiperidin-4-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(6-methyl-5-((2-(4-(4-methylpiperazin-1-yl)phenyl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-ethyl-N-(5-((2-(2-methylthiazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,N-(5-((2-(1-methyl-1H-imidazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(2,2,2-trifluoroethyl)imidazolidine-1-carboxamide,and 3-ethyl-N-(4-methyl-5-((2(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide.18. A pharmaceutical composition, comprising a compound of claim 17 anda pharmaceutically acceptable carrier.
 19. A compound selected from thegroup consisting of3-(2-methoxyethyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(3-methoxypropyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,(S)-3-(1-methoxypropan-2-yl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide,and(R)-3-(1-methoxypropan-2-yl)-N-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide.20. A pharmaceutical composition, comprising a compound of claim 19 anda pharmaceutically acceptable carrier.
 21. A compound selected from thegroup consisting ofN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((2-(1-ethyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,2-oxo-3-(tetrahydro-2H-pyran-4-yl)-N-(5-((2-(1-(trideuteromethyl)-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)imidazolidine-1-carboxamide,N-(5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,N-(5-((6-(1-methyl-1H-pyrazol-4-yl)pyrimidin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide,andN-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide.22. A pharmaceutical composition, comprising a compound of claim 21 anda pharmaceutically acceptable carrier.
 23. The compound of claim 1 whichis3-ethyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide.24. A pharmaceutical composition, comprising the compound of claim 23and a pharmaceutically acceptable carrier.
 25. The compound of claim 1which is3-(2-methoxyethyl)-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide.26. A pharmaceutical composition, comprising the compound of claim 25and a pharmaceutically acceptable carrier.
 27. The compound of claim 1which is3-methyl-N-(6-methyl-5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxoimidazolidine-1-carboxamide.28. A pharmaceutical composition, comprising the compound of claim 27and a pharmaceutically acceptable carrier.
 29. The compound of claim 1which isN-(5-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridin-2-yl)-2-oxo-3-(tetrahydro-2H-pyran-4-yl)imidazolidine-1-carboxamide.30. A pharmaceutical composition, comprising the compound of claim 29and a pharmaceutically acceptable carrier.
 31. A pharmaceuticalcomposition, comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 32. The composition of claim 31 further comprisingan additive selected from adjuvants, excipients, diluents, orstabilizers.
 33. A method of treating cancer, gastrointestinal stromaltumors, hyperproliferative diseases, metabolic diseases,neurodegenerative diseases, solid tumors, melanomas, glioblastomas,ovarian cancer, pancreatic cancer, prostate cancer, lung cancers, breastcancers, renal cancers, hepatic cancers, osteosarcomas, multiplemyelomas, cervical carcinomas, metastasis of primary tumor sites,cancers that are metastatic to bone, papillary thyroid carcinoma,non-small cell lung cancer, colonic cancers, rheumatoid arthritis,osteoarthritis, multiple sclerosis, autoimmune nephritis, lupus, Crohn'sdisease, asthma, chronic obstructive pulmonary disease, osteoporosis,mastocytosis, or mast cell leukemia, the method comprising administeringto a patient in need thereof an effective amount of a compound ofclaim
 1. 34. A method of treating glioblastomas, breast cancers,pancreatic cancers, metastasis of primary tumor sites, or cancers thatare metastatic to bone, the method comprising administering to a patientin need thereof an effective amount of a compound of claim
 1. 35. Themethod of claim 33, wherein the compound is administered orally,parenterally, by inhalation, or subcutaneously.
 36. The method of claim34, wherein the compound is administered orally, parenterally, byinhalation, or subcutaneously.
 37. Use of a compound of claim 1, or apharmaceutically acceptable salt thereof, for the manufacture of amedicament for the treatment of cancer, gastrointestinal stromal tumors,hyperproliferative diseases, metabolic diseases, neurodegenerativediseases, solid tumors, melanomas, glioblastomas, ovarian cancer,pancreatic cancer, prostate cancer, lung cancers, breast cancers, renalcancers, hepatic cancers, osteosarcomas, multiple myelomas, cervicalcarcinomas, metastasis of primary tumor sites, cancers that aremetastatic to bone, papillary thyroid carcinoma, non-small cell lungcancer, colonic cancers, rheumatoid arthritis, osteoarthritis, multiplesclerosis, autoimmune nephritis, lupus, Crohn's disease, asthma, chronicobstructive pulmonary disease, osteoporosis, mastocytosis, or mast cellleukemia.
 38. Use of a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, for the manufacture of a medicament for thetreatment of glioblastomas, breast cancers, pancreatic cancers,metastasis of primary tumor sites, or cancers that are metastatic tobone.